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| United States Patent |
6,127,364
|
|
Dyker
, et al.
|
October 3, 2000
|
1,3,4-oxadiazine derivatives and their use as pesticides
Abstract
The invention relates to novel (1,3,4)-oxadiazine derivatives of formula
(I), to a process and intermediates for their preparation, and to their
usefulness as pesticides, in particular as anthelminthics, insecticides,
acaricides, and nematicides.
| Inventors:
|
Dyker; Hubert (Koln, DE);
Plant; Andrew (Leverkusen, DE);
Scherkenbeck; Jurgen (Wermelskirchen, DE);
Erdelen; Christoph (Leichingen, DE);
Harder; Achim (Koln, DE)
|
| Assignee:
|
Bayer Aktiengesellschaft (Leverkusen, DE)
|
| Appl. No.:
|
142982 |
| Filed:
|
September 18, 1998 |
| PCT Filed:
|
March 17, 1997
|
| PCT NO:
|
PCT/EP97/01325
|
| 371 Date:
|
September 18, 1998
|
| 102(e) Date:
|
September 18, 1998
|
| PCT PUB.NO.:
|
WO97/36883 |
| PCT PUB. Date:
|
October 9, 1997 |
Foreign Application Priority Data
| Mar 29, 1996[DE] | 196 12 644 |
| Current U.S. Class: |
514/229.2; 504/130; 514/228.8; 544/66; 544/68 |
| Intern'l Class: |
C07D 273/04; C07D 498/04; A01N 043/88; C07C 281/02 |
| Field of Search: |
544/68,105,66
504/130
514/229.2
|
References Cited
U.S. Patent Documents
| 4064236 | Dec., 1977 | Dorn et al. | 424/177.
|
| 4670555 | Jun., 1987 | Dekeyser | 544/68.
|
| Foreign Patent Documents |
| 3627161 | Feb., 1987 | DE.
| |
Other References
Liebigs Ann. Chem. (month unavailable) 1981, pp. 1433-1444, Fahr et al,
Azomethin-imine Durch Umsetzung von Diphenylketen mit
Azodicarbonsaureestern.
J. Chem. Soc. Perkins Trans. I, (month unavailable) 1975, pp. 1712-1720,
Dutta et al, Polypeptides. Part XIII. .sup.1 Preparation of
a-Aza-amino-acid (Carbazic Acid) Derivatives and Intermediates for the
Preparation of a-Aza-peptides.
Org. Syntheses Coll., vol. 5, (month unavailable) 1973, pp. 201-204, Staab
et al 1,1'-Carbonyldiimidazole.
Tetrahedron Letters, vol. 28, No. 17, (month unavailable) 1987, pp.
1873-1876, Konz et al, Stereocontrolled Synthesis of D-a-Hydroxy
Carboxylic Acids from L-Amino Acids.
Tetrahedron Letters, vol. 26, No. 43, (month unavailalbe) 1985, pp.
5257-5260, Lerchen et al Stereoselektive Synthese von
D-a-Hydroxycarbonsauren BZW. D-a-Hydroxycarbonsauren Enthaltenden
Depsipeptiden Aus L-Aminosauren.
Compr. Org. Chem. vol. 2, (month unavailable) 1979, pp. 739-778, S.M.
Roberts, Hydroxy and Alkoxy Carboxylic Acids.
Ullmanns Ency. Techn. Chem. 4 .sup.th edition (month unavailable) 1977,
vol. 13, p. 163, Sunmdermann et al, Hydroxycarbonsauren, aromatishe.
J. Am. Chem. Soc. 76, Jul. 26, 1954, Fu et al, pp. 6054-6058, Influence of
Optically Active Acyl Groups on the Enzymatic Hydrolysis of
N-Acylated-L-amino Acids.
Advances in Protein Chemistry, vol. IV, Anson, Edsall (Eds), (month
unavailable), 1948, p. 33, Protein Gels.
IL Farmaco, 50 (6) (month unavailable) 1995, Jacqueline Marchand-Brynaert
et al, pp. 455-469, Design, Synthesis and Evaluation of D,D-Peptidase and
Beta-Lactamase Inhibitors: Azapeptides, Oxapeptides and Related
Heterocycles.
Chemia Analityczna, Warszawa, vol. 17, No. 2, (month unavailable) 1972, pp.
379-385, Jonoforeza Bibulowa Ketonow I Aldehydow W. Postaci
Ksanthydrazonow, Stanislaw Plaza.
|
Primary Examiner: Shah; Mukund J.
Assistant Examiner: Sripada; Pavanaram K
Attorney, Agent or Firm: Gil; Joseph C.
Parent Case Text
This application is a 371 of PCT/EP97/01325 filed Mar. 17, 1997.
Claims
What is claimed is:
1. An oxadiazine derivative of the formula
##STR81##
in which R.sup.1 and R.sup.2 independently of one another each represent a
residue selected from the group consisting of hydrogen, respectively
optionally halogen-substituted alkyl, hydroxyalkyl, alkanoyloxyalkyl,
alkoxyalkyl, arylalkoxyalkyl, mercaptoalkyl, alkylthioalkyl,
alkylsulphinylalkyl, alkylsulphonylalkyl, carboxyalkyl,
alkoxycarbonylalkyl, aryloxycarbonylalkyl, arylalkyloxycarbonylalkyl,
carbamoylalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,
alkoxycarbonylaminoalkyl, alkylcarbonyl, cycloalkylcarbonyl, cycloalkyl,
cycloalkylalkyl, aryl, arylalkyl, arylcarbonyl, and a 5- or 6-membered
hetaryl substituent selected from the group consisting of thienyl,
thiazolyl, or pyridyl, and 5- or 6-membered hetaryl, C.sub.1 -C.sub.4
-alkyl or indolyl-C.sub.1 -C.sub.4 -alkyl, each of which is optionally
substituted by a residue selected from the group consisting of fluorine-,
chlorine-, bromine-, iodine-, hydroxyl-, nitro-, cyano-,amino-, C.sub.1
-C.sub.4 -alkylamino, di-(C.sub.1 -C.sub.4) alkylamino, benzylamino,
dibenzylamino, and protected amino selected from the group consisting of
acetyl-, t-butoxycarbonyl-, benzyloxycarbonyl- or FMOC-amino, C.sub.1
-C.sub.4 -alkoxy and C.sub.1 -C.sub.2 -halogenoalkoxy, or
R.sup.1, R.sup.2 and the two linking nitrogen atoms represent a 5 to 8
membered saturated or unsaturated heterocyclic ring optionally substituted
by a substituent selected from the group consisting of fluorine-,
chlorine-, bromine-, hydroxyl-, nitro-, cyano-, C.sub.1 -C.sub.4 -alkyl-,
C.sub.1 -C.sub.4 -halogenoalkyl-, C.sub.1 -C.sub.4 -alkoxy-, and C.sub.1
-C.sub.2 -halogenoalkoxy,
R.sup.3 and R.sup.4 independently of one another each represent a residue
selected from the group consisting of hydrogen, respectively optionally
halogen-substituted alkyl, alkenyl, hydroxyalkyl, alkanoyloxyalkyl,
alkoxyalkyl, arylalkoxyalkyl, mercaptoalkyl, alkylthioalkyl,
alkylsulphinylalkyl, alkylsulphonylalkyl, alkoxycarbonylalkyl,
aryloxycarbonylalkyl, arylalkyloxycarbonylalkyl, carbamoylalkyl,
aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkylcarbonyl,
cycloalkylcarbonyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, and a 5-
or 6- membered hetaryl, selected from the group consisting of thienyl,
thiazolyl, pyridyl, indolyi, benzo-1,3-dioxolyl, and 5- or 6-membered
hetaryl-C.sub.1 -C.sub.4 -alkyl selected from the group consisting of
thienylmethyl, thiazolylmethyl, imidazolylmethyl, pyridylmethyl,
indolyl-C.sub.1 -C.sub.4 -alkyl, each of which is optionally substituted
by fluorine, chlorine, bromine, iodine, hydroxyl, cyano, C.sub.1 -C.sub.6
-alkyl, C.sub.1 -C.sub.4 -halogenoalkyl, C.sub.1 -C.sub.4 -alkoxy, C.sub.1
-C.sub.4 -halogenoalkoxy, benzyloxy and silyloxy which is trisubstituted
bv C.sub.1 -C.sub.4 -alkyl and/or phenyl or
R.sup.3 and R.sup.4 together represent alkylene or the radical (a)
##STR82##
wherein R.sup.5 and R.sup.6 independently of one another each represent a
residue selected from the group consisting of hydrogen, respectively
optionally halogen substituted alkyl, alkenyl, hydroxyalkyl,
alkanoyloxyalkyl, alkoxyalkyl, arylalkoxyalkyl, mercaptoalkyl,
alkylthioalkyl, alkylsulphinylalkyl, alkylsulphonylalkyl,
alkoxycarbonylalkyl, aryloxycarbonylalkyl, aminoalkyl, alkylaminoalkyl,
dialkylaminoalkyl, alkylcarbonyl, cycloalkyl, cycloalkylalkyl, aryl,
arylalkyl, and 5- or 6-membered hetaryl,
Q.sup.1 and Q.sup.2 independently of one another each represent oxygen or
sulphur, except for 6,6-diphenyl-(1,3,4)-oxadiazinane-2,5-dione.
2. A pesticide formulation for controlling pests selected from the group
consisting of insects, arachnids, nematodes, cestodes, and trematodes
comprising at least one 1,3,4-oxadiazine derivative of the formula (I)
according to claim 1 and at least one suitable carrier.
3. A method for controlling pests and endoparasites selected from the group
consisting of insects, arachnids, nematodes, cestodes, and trematodes
comprising applying 1,3,4-oxadiazine derivatives of the formula (I)
according to claim 1 to pests and endoparasites and/or their habitat.
4. The oxadiazine derivatives of the formula (I) of claim 1 wherein
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, and R.sup.6 are respectively
and independently of one another selected from the group consisting of
substituted cycloalkyl, substituted cycloalkylalkyl, substituted aryl,
substituted arylalkyl, susbtituted arylcarbonyl, substituted
heterocyclylalkyl, substituted hetaryl and substituted hetarylalkyl.
5. A process for preparing the oxadiazine derivative of the formula (I)
according to claim 1,
##STR83##
wherein R.sup.1 and R.sup.2 independently of one another are as defined in
claim 1,
R.sup.1, R.sup.2 and the two linking nitrogen are as defined in claim 1,
R.sup.3 and R.sup.4 independently of one another are as defined in claim 1,
R.sup.3 and R.sup.4 together represent alkylene or the radical (a)
##STR84##
wherein R.sup.5 and R.sup.6 independently of one another are as defined in
claim 1 and
Q.sup.1 is defined as in claim 1 and Q.sup.2 represents oxygen comprising
reacting carbazates of the formula (II)
##STR85##
in which R.sup.1, R.sup.2, R.sup.3, R.sup.3 and Q.sup.1 are as defined
above,
in the presence of a reaction auxiliary and a diluent and optionally in the
presence of a base.
6. The process of preparing oxadiazine derivatives of the formula (I)
according to claim 5 wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5,
and/or R.sup.6 represents cycloalkyl which is substituted with an atom
selected from the group consisting of fluorine, chlorine, and bromine.
7. The process of preparing oxadiazine derivatives of claim 5 wherein
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, and R.sup.6 are respectively
and independently of one another selected from the group consisting of
substituted cycloalkyl, substituted cycloalkylalkyl, substituted aryl,
substituted arylalkyl, susbtituted arylcarbonyl, substituted
heterocyclylalkyl, substituted hetaryl and substituted hetarylalkyl.
8. The oxadiazine derivatives of claim 1 wherein R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, and/or R.sup.6 represents cycloalkyl which is
substituted with an atom selected from the group consisting of fluorine,
chlorine, and bromine.
Description
The invention relates to novel (1,3,4)-oxadiazine derivatives, to a
plurality of processes and intermediates for their preparation and to
their use as pesticides, in particular as anthelmintics, insecticides,
acaricides and nematicides.
Only a single representative of the 2,5-dichalkogeno-(1,3,4)-oxadiazinanes,
6,6-diphenyl-(1,3,4)-oxadiazinane-2,5-dione is hitherto known (Liebigs
Ann. Chem. 1981, 1433).
This invention, accordingly, provides novel (1,3,4)-oxadiazine derivatives
of the formula (I)
##STR1##
in which R.sup.1 and R.sup.2 independently of one another each represent
hydrogen, respectively optionally halogen-substituted alkyl, hydroxyalkyl,
alkanoyloxyalkyl, alkoxyalkyl, arylalkoxyalkyl, mercaptoalkyl,
alkylthioalkyl, alkylsulphinylalkyl, alkylsulphonylalkyl, carboxyalkyl,
alkoxycarbonylalkyl, aryloxycarbonylalkyl, arylalkyloxycarbonylalkyl,
carbamoylalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,
alkoxycarbonylaminoalkyl, alkylcarbonyl, cycloalkylcarbonyl or represent
respectively optionally substituted cycloalkyl, cycloalkylalkyl, aryl,
arylalkyl, arylcarbonyl, heterocyclylalkyl, hetaryl or hetarylalkyl or
R.sup.1, R.sup.2 and the two linking nitrogen atoms represent an optionally
substituted heterocyclic ring,
R.sup.3 and R.sup.4 independently of one another each represent hydrogen,
respectively optionally halogen-substituted alkyl, alkenyl, hydroxyalkyl,
alkanoyloxyalkyl, alkoxyalkyl, arylalkoxyalkyl, mercaptoalkyl,
alkylthioalkyl, alkylsulphinylalkyl, alkylsulphonylalkyl,
alkoxycarbonylalkyl, aryloxycarbonylalkyl, arylalkyloxycarbonylalkyl,
carbamoylalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,
alkylcarbonyl, cycloalkylcarbonyl or represent respectively optionally
substituted cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, hetaryl or
hetarylalkyl or
R.sup.3 and R.sup.4 together represent alkylene or the radical (a)
##STR2##
in which
R.sup.5 and R.sup.6 independently of one another each represent hydrogen,
respectively optionally halogen-substituted alkyl, alkenyl, hydroxyalkyl,
alkanoyloxyalkyl, alkoxyalkyl, arylalkoxyalkyl, mercaptoalkyl,
alkylthioalkyl, alkylsulphinylalkyl, alkylsulphonylalkyl,
alkoxycarbonylalkyl, aryloxycarbonylalkyl, aminoalkyl, alkylaminoalkyl,
dialkylaminoalkyl, alkylcarbonyl or represent respectively optionally
substituted cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, hetaryl or
hetarylalkyl and
Q.sup.1 and Q.sup.2 independently of one another each represent oxygen or
sulphur,
except for 6,6-diphenyl-(I,3,4)-oxadiazinane-2,5-dione.
Depending inter alia on the nature of the substituents, the compounds of
the formula (I) may be present as geometric and/or optical isomers or
mixtures of isomers, in varying compositions, which can, if appropriate,
be separated in a customary manner. The present invention provides both
the pure isomers and the isomer mixtures, their preparation and their use
and compositions comprising them. Hereinbelow, for the sake of simplicity,
reference is however always made to compounds of the formula (I) although
this includes both the pure isomers and, if appropriate, also mixtures
having varying proportions of isomeric compounds.
Furthermore, it has been found that the novel compounds of the formula (I)
are obtained by one of the processes described below.
A) (1,3,4)-Oxadiazine derivatives of the formula (I-a)
##STR3##
in which
R.sup.1 to R.sup.4 and Q.sup.1 are each as defined above,
can be prepared by reacting carbazates of the formula (II)
##STR4##
in which
R.sup.1 to R.sup.4 and Q.sup.1 are each as defined above,
in the presence of a reaction auxiliary and a diluent and, if appropriate,
in the presence of a base.
B) (1,3,4)-Oxadiazine derivatives of the formula (I-b)
##STR5##
in which
R.sup.1 to R.sup.3, Q.sup.1 and Q.sup.2 are each as defined above and
R.sup.4-1 represents the same radicals as R.sup.4, with the exception of 10
hydrogen,
can be prepared by reacting
(1,3,4)-oxadiazine derivatives of the formula (I-c)
##STR6##
in which
R.sup.1 and R.sup.2 have meanings other than hydrogen,
R.sup.3, Q.sup.1 and Q.sup.2 are each as defined above,
with compounds of the formula (III)
R.sup.4-1 -E (III),
in which
R.sup.4-1 is as defined above and
E represents an electron-withdrawing leaving group,
if appropriate in the presence of a diluent and, if appropriate, in the
presence of a reaction auxiliary.
C) (1,3,4)-Oxadiazine derivatives of the formula (I-d)
##STR7##
in which
R.sup.1 to R.sup.3, Q.sup.1 and Q.sup.2 are each as defined above and
R.sup.4-2 represents the radical (b)
##STR8##
in which
R.sup.5 and R.sup.6 independently of one another each represent hydrogen,
optionally substituted alkyl or aryl, or
R.sup.3 and R.sup.4-2 together represent the radical (a)
##STR9##
in which
R.sup.5 and R.sup.6 are each as defined above,
can be prepared by reacting
(1,3,4)-oxadiazine derivatives of the formula (I-c)
##STR10##
in which
R.sup.1 to R.sup.3, Q.sup.1 and Q.sup.2 are each as defined above
with ketones or aldehydes of the formula (IV)
R.sup.5 --CO--R.sup.6 (IV),
in which
R.sup.5 and R.sup.6 are each as defined above,
if appropriate in the presence of a diluent and, if appropriate, in the
presence of a reaction auxiliary, and subsequently, if appropriate,
eliminating water.
D) (1,3,4)-Oxadiazine derivatives of the formula (I-e)
##STR11##
in which
R.sup.1-1 represents the same radicals as R.sup.1, with the exception of
hydrogen,
R.sup.2 to R.sup.4, Q.sup.1 and Q.sup.2 are each as defined above,
can be prepared by reacting (1,3,4)-oxadiazine derivatives of the formula
(I-f)
##STR12##
in which
R.sup.2 to R.sup.4, Q.sup.1 and Q.sup.2 are each as defined above,
with compounds of the formula (V)
R.sup.1-1 -E (V),
in which
R.sup.1-1 is as defined above and
E represents an electron-withdrawing leaving group,
if appropriate in the presence of a diluent and, if appropriate, in the
presence of a reaction auxiliary.
E) (1,3,4)-Oxadiazine derivatives of the formula (I-g)
##STR13##
in which
R.sup.1, R.sup.3, R.sup.4, Q.sup.1 and Q.sup.2 are each as defined above
and
R.sup.2-1 represents the same radicals as R.sup.2, with the exception of
hydrogen,
can be prepared by reacting (1,3,4)-oxadiazine derivatives of the formula
(I-h)
##STR14##
in which
R.sup.1, R.sup.3, R.sup.4, Q and Q.sup.1 are each as defined above,
with compounds of the formula (VI)
R.sup.2-1 -E (VI),
in which
R.sup.2-1 is as defined above and
E represents an electron-withdrawing leaving group,
if appropriate in the presence of a diluent and, if appropriate, in the
presence of a reaction auxiliary.
F) (1,3,4)-Oxadiazine derivatives of the formula (I)
##STR15##
in which
R.sup.1 to R.sup.4, Q.sup.1 and Q.sup.2 are each as defined above,
can be prepared by reacting and cyclocondensing compounds of the formula
(VII)
##STR16##
in which
R.sup.1 to R.sup.4 and Q.sup.2 are each as defined above,
with compounds of the formula (VIII)
##STR17##
in which
Y.sup.1 represents chlorine, trichloromethoxy, C.sub.1 -C.sub.4 -alkoxy,
optionally substituted phenoxy, 1-imidazolyl or 1,2,4-triazolyl and
Y.sup.2 represents chlorine, trichloromethoxy, 1-imidazolyl or
1,2,4-triazolyl,
Q.sup.1 is as defined above,
if appropriate in the presence of a diluent and, if appropriate, in the
presence of a reaction auxiliary.
G) (1 ,3,4)-Oxadiazine derivatives of the formula (I)
##STR18##
in which
R.sup.1 to R.sup.4, Q.sup.1 and Q.sup.2 are each as defined above,
can be prepared by cyclocondensing compounds of the formula (IX)
##STR19##
in which
R.sup.1 to R.sup.4, Q.sup.1, Q.sup.2 and Y.sup.1 are each as defined above,
if appropriate in the presence of a diluent and, if appropriate, in the
presence of a reaction auxiliary.
H) (1,3,4)-Oxadiazine derivatives of the formula (I-i)
##STR20##
in which
R.sup.1 to R.sup.4 and Q.sup.1 are each as defined above,
can be prepared by reacting (1,3,4)-oxadiazine derivatives of the formula
##STR21##
in which
R.sup.1 to R.sup.4 and Q are each as defined above,
with a thionylating reagent, if appropriate in the presence of a diluent.
Furthermore, it has been found that the novel compounds of the formula (I)
have very high activity as pesticides, preferably for controlling
endoparasites in useful animals and for controlling insects, arachnids and
nematodes encountered in agriculture, in forests, in the protection of
stored products and materials and in the hygiene sector.
The formula (I) provides a general definition of the compounds according to
the invention. Preferred substituents and ranges of the radicals listed in
the formulae mentioned hereinabove and hereinbelow are illustrated below.
R.sup.1 and R.sup.2 independently of one another each preferably represent
hydrogen, C.sub.1 -C.sub.15 -alkyl, in particular also
3,7,11-trimethyldodecyl, represent respectively optionally fluorine-,
chlorine- or bromine-substituted C.sub.1 -C.sub.8 -alkyl, C.sub.3 -C.sub.7
-cycloalkyl, C.sub.3 -C.sub.7 -cycloalkyl-C.sub.1 -C.sub.4 -alkyl, C.sub.1
-C.sub.6 -hydroxyalkyl, C.sub.1 -C.sub.4 -alkanoyloxy-C.sub.1 -C.sub.6
-alkyl, C.sub.1 -C.sub.4 -alkoxy-C.sub.1 -C.sub.6 -alkyl, aryl-C.sub.1
-C.sub.4 -alkoxy-C.sub.1 -C.sub.6 -alkyl, C.sub.1 -C.sub.6 -mercaptoalkyl,
in particular mercaptomethyl, C.sub.1 -C.sub.4 -alkylthio-C.sub.1 -C.sub.6
-alkyl, in particular methylthioethyl, C.sub.1 -C.sub.4
-alkylsulphinyl-C.sub.1 -C.sub.6 -alkyl, in particular
methylsulphinylethyl, C.sub.1 -C.sub.4 -alkylsulphonyl-C.sub.1 -C.sub.6
-alkyl, in particular methylsulphonylethyl, carboxy-C.sub.1 -C.sub.6
-alkyl, in particular carboxymethyl or carboxyethyl, C.sub.1 -C.sub.4
-alkoxycarbonyl-C.sub.1 -C.sub.6 -alkyl, in particular
methoxycarbonylmethyl orethoxycarbonylethyl, aryloxycarbonyl-C.sub.1
-C.sub.6 -alkyl, in particular phenoxycarbonylmethyl, aryl-C.sub.1
-C.sub.4 -alkyloxycarbonyl-C.sub.1 -C.sub.6 -alkyl, in particular
benzyloxycarbonylmethyl, carbamoyl-C.sub.1 -C.sub.6 -alkyl, in particular
carbamoylmethyl or carbamoylethyl, amino-C.sub.1 -C.sub.6 -alkyl, in
particular aminopropyl or aminobutyl, C.sub.1 -C.sub.4 -alkylamino-C.sub.1
-C.sub.6 -alkyl in particular methylaminopropyl or methylamino,
di-(C.sub.1 -C.sub.4)-alkylamino-C.sub.1 -C.sub.6 -alkyl in particular
dimethylaminopropyl or dimethylaminobutyl, C.sub.1 -C.sub.4
-alkoxycarbonylamino-C.sub.1 -C.sub.6 -alkyl, C.sub.1 -C.sub.6
-alkylcarbonyl, C.sub.3 -C.sub.7 -cycloalkylcarbonyl or represent aryl,
aryl-C.sub.1 -C.sub.4 -alkyl, arylcarbonyl, aryl-C.sub.1 -C.sub.4
-alkylcarbonyl, hetaryl or hetaryl-C.sub.1 -C.sub.4 -alkyl, where
optionally one NH function in the heterocyclic ring may be derivatized by
an amino protective group such as, for example, those mentioned above,
each of which is optionally substituted by halogen, hydroxyl, nitro,
cyano, amino, C.sub.1 -C.sub.4 -alkylamino, di-(C.sub.1
-C.sub.4)-alkylamino, benzylamino, dibenzylamino, protected amino such as,
for example, acetyl-, t-butoxycarbonyl-, benzyloxycarbonyl- or FMOC-amino,
C.sub.1 -C.sub.6 -alkyl, C.sub.1 -C.sub.4 -halogenoalkyl, C.sub.1 -C.sub.4
-alkoxy or C.sub.1 -C.sub.4 -halogenoalkoxy. and optionally C.sub.1
-C.sub.4 -alkyl-substituted heterocyclyl-C.sub.1 -C.sub.4 -alkyl such as,
for example, dioxolanylmethyl.
R.sup.1 and R.sup.2 together with the two linking nitrogen atoms preferably
represent an optionally halogen-, hydroxyl-, nitro-, cyano-, C.sub.1
-C.sub.4 -alkyl-, C.sub.1 -C.sub.4 -halogenoalkyl-, C.sub.1 -C.sub.4
-alkoxy- or C.sub.1 -C.sub.4 -halogenoalkoxy-substituted 5- to 8-membered
saturated or unsaturated heterocyclic ring.
R.sup.3 and R.sup.4 independently of one another each preferably represent
hydrogen, C.sub.1 -C.sub.6 -alkyl, represent respectively optionally
fluorine-, chlorine- or bromine- substituted C.sub.1 -C.sub.6 -alkyl,
C.sub.2 -C.sub.8 -alkenyl, C.sub.3 -C.sub.7 -cycloalkyl, C.sub.3 -C.sub.7
-cycloalkyl-C.sub.1 -C.sub.4 -alkyl, C.sub.1 -C.sub.6 -hydroxyalkyl,
C.sub.1 -C.sub.4 -alkanoyloxy-C.sub.1 -C.sub.6 -alkyl in particular
acetoxymethyl or 1-acetoxyethyl, C.sub.1 -C.sub.4 -alkoxy-C.sub.1 -C.sub.6
-alkyl in particular methoxymethyl or 1-methoxyethyl, aryl-C.sub.1
-C.sub.4 -alkoxy-C.sub.1 -C.sub.6 -alkyl, C.sub.1 -C.sub.6 -mercaptoalkyl,
in particular mercaptomethyl, C.sub.1 -C.sub.4 -alkylthio-C.sub.1 -C.sub.6
-alkyl, in particular methylthioethyl, C.sub.1 -C.sub.4
-alkylsulphinyl-C.sub.1 -C.sub.6 -alkyl, in particular
methylsulphinylethyl, C.sub.1 -C.sub.4 -alkylsulphonyl-C.sub.1 -C.sub.6
-alkyl, in particular methylsulphonylethyl, C.sub.1 -C.sub.4
-alkoxycarbonyl-C.sub.1 -C.sub.6 -alkyl, aryloxycarbonyl-C.sub.1 -C.sub.6
-alkyl, in particular phenoxycarbonylmethyl, aryl-C.sub.1 -C.sub.4
-alkyloxycarbonyl-C.sub.1 -C.sub.6 -alkyl, carbamoyl-C.sub.1 -C.sub.6
-alkyl, in particular carbamoylmethyl or carbamoylethyl, amino-C.sub.1
-C.sub.6 -alkyl, C.sub.1 -C.sub.4 -alkylamino-C.sub.1 -C.sub.6 -alkyl,
di-C.sub.1 -C.sub.4 -alkylamino-C.sub.1 -C.sub.6 -alkyl, C.sub.1 -C.sub.6
-alkylcarbonyl, C.sub.3 -C.sub.7 -cycloalkylcarbonyl, or represent aryl,
aryl-C.sub.1 -C.sub.4 -alkyl, arylcarbonyl, hetaryl or hetaryl-C.sub.1
-C.sub.4 -alkyl, each of which is optionally substituted by halogen,
hydroxyl, cyano, C.sub.1 -C.sub.6 -alkyl, C.sub.1 -C.sub.4 -halogenoalkyl,
C.sub.1 -C.sub.4 -alkoxy, C.sub.1 -C.sub.4 -halogenoalkoxy, benzyloxy or
silyloxy which is trisubstituted by C.sub.1 -C.sub.4 -alkyl and/or phenyl.
R.sup.3 and R.sup.4 together preferably represent C.sub.2 -C.sub.7
-alkylene or the radical (a)
##STR22##
in which
R.sup.5 and R.sup.6 independently of one another each represent hydrogen,
respectively optionally fluorine-, chlorine- or bromine-substituted
C.sub.1 -C.sub.6 -alkyl, C.sub.2 -C.sub.4 -1-alkenyl or C.sub.3 -C.sub.7
-cycloalkyl or represent respectively optionally halogen-, hydroxyl-,
nitro-, C.sub.1 -C.sub.6 -alkyl-, C.sub.1 -C.sub.4 -halogenoalkyl-,
C.sub.1 -C.sub.4 -alkoxy-, C.sub.1 -C.sub.4 -halogenoalkoxy-, phenoxy-,
amino-, C.sub.1 -C.sub.4 -alkylamino- or di-(C.sub.1
-C.sub.4)-alkylamino-substituted phenyl, phenyl-C.sub.1 -C.sub.4 -alkyl or
5- or 6-membered hetaryl.
Q.sup.1 and Q.sup.2 independently of one another each preferably represent
oxygen or sulphur.
6,6-Diphenyl-(1,3,4)-oxadiazinane-2,5-dione is excluded from the preferred
range.
R.sup.1 and R.sup.2 independently of one another each particularly
preferably represent hydrogen, C.sub.1 -C.sub.10 -alkyl, represent
respectively optionally fluorine-, chlorine- or bromine-substituted
C.sub.1 -C.sub.4 -alkyl, C.sub.3 -C.sub.7 -cycloalkyl, in particular
cyclopentyl, cyclohexyl or cycloheptyl, C.sub.3 -C.sub.7
-cycloalkyl-C.sub.1 -C.sub.4 -alkyl, C.sub.1 -C.sub.6 -hydroxyalkyl, in
particular hydroxymethyl or 1-hydroxyethyl, C.sub.1 -C.sub.4
-alkanoyloxy-C.sub.1 -C.sub.6 -alkyl, in particular acetoxymethyl or
1-acetoxyethyl, C.sub.1 -C.sub.4 -alkoxy-C.sub.1 -C.sub.6 -alkyl, in
particular methoxymethyl or 1-methoxyethyl, phenyl-C.sub.1 -C.sub.4
-alkoxy-C.sub.1 -C.sub.6 -alkyl, in particular benzyloxymethyl or
1-benzyloxyethyl, C.sub.1 -C.sub.4 -alkoxycarbonylamino-C.sub.1 -C.sub.6
-alkyl, in particular tert-butoxycarbonylaminopropyl or
tert-butoxycarbonylaminobutyl, C.sub.1 -C.sub.6 -alkylcarbonyl, in
particular acetyl, propionyl or butyryl, C.sub.3 -C.sub.7
-cycloalkylcarbonyl, in particular cyclopropylcarbonyl or
cyclohexylcarbonyl, or represent phenyl, phenyl-C.sub.1 -C.sub.4 -alkyl,
phenylcarbonyl, 5- or 6-membered hetaryl, in particular thienyl, thiazolyl
or pyridyl, 5- or 6-membered hetaryl-C.sub.1 -C.sub.4 -alkyl or
indolyl-C.sub.1 -C.sub.4 -alkyl, each of which is optionally substituted
by fluorine, chlorine, bromine, iodine, hydroxyl, nitro, cyano, amino,
C.sub.1 -C.sub.4 -alkylamino, di-(C.sub.1 -C.sub.4)-alkylamino,
benzylamino, dibenzylamino, protected amino such as, for example, acetyl-,
t-butoxycarbonyl-, benzyloxycarbonyl- or FMOC-amino, C.sub.1 -C.sub.4
-alkyl, C.sub.1 -C.sub.4 -halogenoalkyl, C.sub.1 -C.sub.4 -alkoxy or
C.sub.1 -C.sub.2 -halogenoalkoxy.
R.sup.1 and R.sup.2 together with the two linking nitrogen atoms
particularly preferably represent an optionally fluorine-, chlorine-,
bromine-, hydroxyl-, nitro-, cyano-, C.sub.1 -C.sub.4 -alkyl-, C.sub.1
-C.sub.4 -halogenoalkyl-, C.sub.1 -C.sub.4 -alkoxy- or C-C.sub.2
-halogenoalkoxy-substituted 5- to 8-membered saturated or unsaturated
heterocyclic ring.
R.sup.3 and R.sup.4 independently of one another each particularly
preferably represent hydrogen, C.sub.1 -C.sub.12 -alkyl, represent
respectively optionally fluorine-, chlorine- or bromine-substituted
C.sub.1 -C.sub.4 -alkyl, C.sub.2 -C.sub.6 -alkenyl, C.sub.3 -C.sub.7
-cycloalkyl, in particular cyclopentyl, cyclohexyl or cycloheptyl, C.sub.3
-C.sub.7 -cycloalkyl-C.sub.1 -C.sub.4 -alkyl, C.sub.1 -C.sub.6
-hydroxyalkyl, phenyl-C.sub.1 -C.sub.4 -alkoxy-C.sub.1 -C.sub.6 -alkyl, in
particular benzyloxymethyl or 1-benzyloxyethyl, C.sub.1 -C.sub.4
-alkylthio-C.sub.1 -C.sub.6 -alkyl, in particular methylthioethyl, C.sub.1
-C.sub.4 -alkoxycarbonyl-C.sub.1 -C.sub.6 -alkyl, in particular
methoxycarbonylmethyl or ethoxycarbonylethyl, phenyl-C.sub.1 -C.sub.4
-alkyloxycarbonyl-C.sub.1 -C.sub.6 -alkyl, in particular
benzyloxycarbonylmethyl, amino-C.sub.1 -C.sub.6 -alkyl, in particular
aminopropyl or aminobutyl, C.sub.1 -C.sub.4 -alkylamino-C.sub.1 -C.sub.6
-alkyl, in particular methylaminopropyl or methylaminobutyl, di-(C.sub.1
-C.sub.4)-alkylamino-C.sub.1 -C.sub.6 -alkyl, in particular
dimethylaminopropyl or dimethylaminobutyl, C.sub.1 -C.sub.6
-alkylcarbonyl, in particular acetyl, propionyl or butyryl, C.sub.3
-C.sub.7 -cycloalkylcarbonyl, in particular cyclopropylcarbonyl or
cyclohexylcarbonyl or represent phenyl, phenyl-C.sub.1 -C.sub.4 -alkyl,
naphthylmethyl, phenylcarbonyl, 5- or 6-membered hetaryl, in particular
thienyl, thiazolyl or pyridyl, indolyl, benzo-1,3-dioxolyl, 5- or
6-membered hetaryl-C.sub.1 -C.sub.4 -alkyl in particular thienylmethyl,
thiazolylmethyl, imidazolylmethyl or pyridylmethyl or indolyl-C.sub.1
-C.sub.4 -alkyl, each of which is optionally substituted by fluorine,
chlorine, bromine, iodine, hydroxyl, cyano, C.sub.1 -C.sub.6 -alkyl,
C.sub.1 -C.sub.4 -halogenoalkyl, C.sub.1 -C.sub.4 -alkoxy, C.sub.1
-C.sub.4 -halogenoalkoxy, benzyloxy or silyloxy which is trisubstituted by
C.sub.1 -C.sub.4 -alkyl and/or phenyl.
R.sup.3 and R.sup.4 together particularly preferably represent C.sub.2
-C.sub.6 -alkylene or the radical (a)
##STR23##
in which
R.sup.5 and R.sup.6 independently of one another each represent hydrogen,
respectively optionally fluorine-, chlorine- or bromine-substituted
C.sub.1 -C.sub.4 -alkyl or C.sub.3 -C.sub.6 -cycloalkyl, in particular
cyclopropyl, cyclopentyl or cyclohexyl, or represent respectively
optionally fluorine-, chlorine-, bromine-, hydroxyl, nitro-, C.sub.1
-C.sub.4 -alkyl-, C.sub.1 -C.sub.4 -halogenoalkyl-, C.sub.1 -C.sub.4
-alkoxy-, C.sub.1 -C.sub.4 -halogenoalkoxy-, phenoxy-, amino-, C.sub.1
-C.sub.4 -alkylamino-, in particular methylamino- or ethylamino- or
di-(C.sub.1 -C.sub.4)-alkylamino-, in particular dimethylamino- or
diethylamino-substituted phenyl, phenyl-C.sub.1 -C.sub.4 -alkyl or 5- or
6-membered hetaryl.
Q.sup.1 particularly preferably represents oxygen or sulphur.
Q.sup.2 particularly preferably represents oxygen.
6,6-Diphenyl-(I,3,4)-oxadiazinane-2,5-dione is excluded from the
particularly preferred range.
R.sup.1 and R.sup.2 independently of one another each very particularly
preferably represent hydrogen, C.sub.1 -C.sub.10 -alkyl, in particular
methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,
tert-butyl, n-pentyl, isopentyl, sec-pentyl, tert-pentyl, n-hexyl,
isohexyl, sec-hexyl, n-heptyl, isoheptyl, sec-heptyl, oktyl, isooctyl,
secoctyl or 3,7-dimethyloctyl, represent C.sub.3 -C.sub.7
-cycloalkyl-C.sub.1 -C.sub.4 -alkyl in particular cyclopentylmethyl,
cyclohexylmethyl or cycloheptylmethyl, represent respectively optionally
fluorine-, chlorine-, bromine-, iodine-, hydroxyl-, cyano-, methyl-,
ethyl-, n-propyl-, isopropyl-, n-butyl-, isobutyl-, sec-butyl-,
tert-butyl-, trifluoromethyl-, trichloromethyl-, methoxy-,
difluoromethoxy-, trifluoromethoxy- or benzyloxy-substituted phenyl,
benzyl, phenethyl, 5- or 6-membered hetarylmethyl, in particular
thienylmethyl, thiazolylmethyl, furylmethyl or pyridylmethyl or represent
indolylmethyl.
R.sup.1 and R.sup.2 together with the two linking nitrogen atoms very
particularly preferably represent a 5- or 6-membered saturated or
unsaturated heterocyclic ring, in particular --(CH.sub.2).sub.3 -- and
--(CH.sub.2).sub.4 --.
R.sup.3 and R.sup.4 independently of one another each very particularly
preferably represent hydrogen, C.sub.1 -C.sub.12 -alkyl, in particular
methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,
tert-butyl, n-pentyl, isopentyl, sec-pentyl, tert-pentyl, n-hexyl,
isohexyl, sec-hexyl, n-heptyl, isoheptyl, sec-heptyl, oktyl, isooctyl,
secoctyl, n-decyl or n-dodecyl, represent respectively optionally
fluorine- or chlorine-substituted C.sub.1 -C.sub.4 -alkyl, in particular
fluoromethyl, trifluoromethyl or trichloromethyl, represent C.sub.2
-C.sub.6 -alkenyl, in particular vinyl or allyl, represent cyclopentyl or
cyclohexyl, represent C.sub.3 -C.sub.7 -cycloalkyl-C.sub.1 -C.sub.4
-alkyl, in particular cyclopropylmethyl, represent methylthioethyl or
represent respectively optionally fluorine-, chlorine-, bromine-, iodine-,
hydroxyl-, cyano-, methyl-, ethyl-, n-propyl-, isopropyl-, n-butyl-,
isobutyl-, sec-butyl-, tert-butyl-, trifluoromethyl-, trichloromethyl-,
methoxy-, difluoromethoxy-, trifluoromethoxy- or benzyloxy-substituted
phenyl, phenyl-C.sub.1 -C.sub.4 -alkyl, in particular benzyl,
3-naphthylmethyl, benzo-1,3-dioxol-5-yl, thienylmethyl, imidazolylmethyl
or indolylmethyl.
R.sup.3 and R.sup.4 together very particularly preferably represent
--(CH.sub.2).sub.2 --, --CH(CH.sub.3)CH.sub.2 --, --C(CH.sub.3).sub.2
CH.sub.2 --, --(CH.sub.2).sub.3 --, --(CH.sub.2).sub.4 --,
--(CH.sub.2).sub.5 -- or the radical (a)
##STR24##
in which
R.sup.5 and R.sup.6 independently of one another each represent hydrogen,
represent optionally fluorine- or chlorine-substituted methyl, ethyl,
n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl or
represent respectively optionally fluorine-, chlorine-, bromine-, nitro-,
amino-, methyl-, ethyl-, trifluoromethyl-, methoxy-, difluoromethoxy- or
trifluoromethoxy-substituted phenyl, benzyl or pyridyl.
6,6-Diphenyl-(1,3,4)-oxadiazinane-2,5-dione is excluded from the very
particularly preferred range.
The general or preferred radical definitions or illustrations listed above
can be combined with each other at will, i.e. combinations between the
given ranges and preferred ranges are also possible. These radical
definitions or illustrations apply both to the end products and, in a
corresponding manner, to the starting materials and intermediates.
Preference according to the invention is given to those compounds of the
formula (I) which contain a combination of the definitions listed above as
being preferred.
Particular preference according to the invention is given to those
compounds of the formula (I) which contain a combination of the
definitions listed above as being particularly preferred.
Very particular preference according to the invention is given to those
compounds of the formula (I) which contain a combination of the
definitions listed above as being very particularly preferred.
Saturated or unsaturated hydrocarbon radicals such as alkyl and alkenyl may
be, including in combination with hetero atoms such as in alkoxy, for
example, straight-chain or branched in each case as far as this is
possible.
Optionally substituted radicals may be mono- or polysubstituted, it being
possible for the substituents in the case of polysubstitution to be
identical or different.
Using, for example,
3-methoxy-2-methyl-2-(tetrahydropyridazine-1-carbothionyloxy)-propionic
acid as starting material, the course of the reaction in the process (A)
according to the invention can be represented by the following equation:
##STR25##
Using, for example,
3-tert-butyl-4-(2-thienylmethyl)-2,5-dioxo-(1,3,4)-oxadiazine and benzyl
bromide as starting materials, the course of the reaction in the process
(B) according to the invention can be represented by the following
equation:
##STR26##
Using, for example, 3,4-dimethyl-2,5-dioxo-(1,3,4)-oxadiazine and acetone
as starting materials, the course of the reaction in the process (C)
according to the invention can be represented by the following equation:
##STR27##
Using, for example, 4,6-dimethyl-6-vinyl-2,5-dioxo-(1,3,4)-oxadiazine and
iodomethane as starting materials, the course of the reaction in the
process (D) according to the invention can be represented by the following
equation:
##STR28##
Using, for example,
3-methyl-6-(2-methylpropyl)-2,5-dioxo-(1,3,4)-oxadiazine and dimethyl
sulphate as starting materials, the course of the reaction in the process
(E) according to the invention can be represented by the following
equation:
##STR29##
Using, for example,
2'-(4-chlorophenyl)-1'-methyl-(1-hydroxy-2-methyl-cyclopropane)carbohydraz
ide and phosgene as starting materials, the course of the reaction in the
process (F) according to the invention can be represented by the following
equation:
##STR30##
Using, for example,
1'-phenyl-2'-methyl-[3-methyl-2-(4-nitrophenoxycarbonyloxy)]-butyrohydrazi
de as starting material, the course of the reaction in the process (G)
according to the invention can be represented by the following equation:
##STR31##
Using, for example,
4-(4-methylpentyl)-3-methyl-6-phenyl-2,5-dioxo-(1,3,4)-oxadiazine and
[2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetan-2,4-dithione
(Lawesson's reagent) as starting materials, the course of the reaction in
the process (H) according to the invention can be represented by the
following equation:
##STR32##
The formula (II) provides a general definition of the carbazates required
for carrying out the process (A) according to the invention. In this
formula, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and Q.sup.1 each preferably
represent those radicals which have already been mentioned above, in
connection with the description of the oxadiazine derivatives of the
formula (I), as being preferred substituents. The carbazates of the
formula (II) are novel, except for the compounds in which simultaneously
R.sup.2 and R.sup.4 each represent hydrogen, R.sup.1 represents C.sub.1
-C.sub.5 -alkyl and R.sup.3 represents methyl or benzyl (cf. DE-OS (German
Published Specification) 2 658 254).
Carbazates of the formula (II) can be prepared, for example, by cleaving
off the protective group A.sup.2 of C-terminal protected carbazates of the
formula (X) in a process (A.a) according to the following equation:
##STR33##
In the formula (XI), A.sup.2 represents a C-terminal protective group such
as, for example, tert-butyl or benzyl (cf., for example, T. W. Greene, P.
G. M. Wuts, Protective Groups in Organic Synthesis, 2 ed., John Wiley &
Sons, New York 1991).
The reaction can be carried out by customary methods for C-terminal
deblocking such as acidolysis, for example in the case of a tert-butyl
ester, or catalytic hydrogenation, for example in the case of a benzyl
ester.
Carbazates of the formula (II) can also be prepared, for example, by
cleaving off the protective group A.sup.3 of N-terminal protected
carbazates of the formula (XI) in a process (A.b) according to the
following equation:
##STR34##
In the formula (X), A.sup.3 represents an N-terminal protective group such
as, for example, tert-butoxycarbonyl (BOC), benzyloxycarbonyl (Cbz) or
benzyl (Bzl) (cf., for example, T. W. Greene, P. G. M. Wuts, Protective
Groups in Organic Synthesis, 2 ed., John Wiley & Sons, New York 1991).
The reaction can be carried out by customary methods for N-terminal
deblocking such as acidolysis, for example in the case of the BOC group,
or catalytic hydrogenation, for example in the case of a benzyl ester.
The O-terminal protected carbazates of the formula (X) required for
carrying out the process (A.a) or the N-terminal protected carbazates of
the formula (XI) required for carrying out the process (A.b) can be
prepared starting from N- and 0-termninal protected carbazates of the
formula (XII)
##STR35##
by either cleaving the N-terminal protective group in a process (A.a.b)
similar to (A.b) or by cleaving the 0-terminal protective group in a
process (A.b.a) similar to (A.a). Depending on the nature of the
protective group, it is also possible, in a particular embodiment of the
process, to cleave both protective groups in one step and to convert
compounds of the formula (XII) directly into compounds of the formula (II)
(process A.a/b).
Compounds of the formula (XII) can be prepared, for example, by reacting
compounds of the formula (XIII) with carbazates or hydrazines of the
formula (XIV), if appropriate in the presence of a diluent, according to
the following equation:
##STR36##
In the formula (XIII), Y.sup.1 represents chlorine, trichloromethoxy,
C.sub.1 -C.sub.4 -alkoxy, optionally substituted phenoxy, 1-imidazolyl or
1,2,4-triazolyl.
Some of the carbazates or hydrazines of the formula (XIV) are known or can
be prepared by known methods (cf., for example, J. Chem. Soc. Perkin
Trans. I 1975, 1712).
Compounds of the formulae (X) and (XII) are novel, except for the compounds
in which R.sup.2, R.sup.4 each represent hydrogen, R.sup.1 represents
C.sub.1 -C.sub.5 -alkyl and R.sup.3 represents methyl or benzyl.
Compounds of the formula (XIII) can be prepared, for example, by reacting
protected .alpha.-hydroxycarboxylic acids of the formula (XV) with
compounds of the formula (VIII) according to the following equation:
##STR37##
In the formula (VIII), Y.sup.2 represents chlorine, trichloromethoxy,
1-imidazolyl or 1,2,4-triazolyl. The compounds of the formula (VIII) are
generally known reagents for (thio)phosgenations (cf., for example, Org.
Syntheses Coll. Vol. 5, 201 (1973)).
The protected a-hydroxycarboxylic acids of the formula (XV) can be prepared
from the free carboxylic acids by generally known methods (for example
esterification using alkyl halides or benzyl halides in the presence of
caesium carbonate, J. Chem. Soc. Perkin Trans. 1 1993, 11).
.alpha.-Hydroxycarboxylic acids are commercially available or can be
prepared, for example, from a-amino acids via deamination (cf., for
example, Tetrahedron Letters 28, 1873 (1987) and 26, 5257 (1985); Compr.
Org. Chem. Vol. 2, 739-778 (1979); Ullmanns Encyclopadie Techn. Chem. 4th
ed. (1977), Volume 13, 163).
Compounds of the formula (XII) in which Q.sup.1 represents oxygen (XII-1)
can also be c prepared, for example, by reacting compounds of the formula
(XVI) with the formula (XVII), if appropriate in the presence of a
diluent, according to the following equation:
##STR38##
In the formula (XVI), Me.sup.1 represents an alkali metal, preferably
potassium or caesium. In the formula (XVII), X represents chlorine,
bromine, alkanesulphonyl, in particular methanesulphonyl or
trifluoromethanesulphonyl or arenesulphonyl, in particular
benzenesulphonyl or p-toluenesulphonyl.
Compounds of the formula (XVI) can be prepared by reacting the carbazates
or hydrazines of the formula (XIV) described further above with alkali
metal carbonates, preferably potassium carbonate or caesium carbonate, if
appropriate in the presence of carbon dioxide.
Compounds of the formula (XVII) can be prepared, for example, by generally
known methods from the abovementioned derivatives of a-hydroxycarboxylic
acids. Furthermore, compounds of the formula (XVII) in which X represents
bromine or chlorine can be prepared, for example, by initially converting
a-amino acids into .alpha.-chloro- or bromo-carboxylic acids (cf. J. Am.
Chem. Soc. 76, 6054 (1954); Advances in Protein Chemistry Vol. IV, M. L.
Anson, J. T. Edsall (Eds.) 1948, 33) and protecting these by generally
known methods.
The oxadiazines of the formula (I-c) required for carrying out the
processes (B) and (C) according to the invention constitute a sub-group of
the compounds of the general formula (I) according to the invention and
can be prepared, for example, by processes (A) and (D) to (H).
The formula (III) provides a general definition of the compounds
furthermore required for carrying out the process (B). In this formula,
R.sup.4-l preferably represents the radicals which have already been
mentioned, in connection with the description of the oxadiazine
derivatives of the formula (I), as being preferred for R.sup.4, with the
exception of hydrogen. E preferably represents halogen, in particular
chlorine or bromine, in the case where R.sup.4-1 represents one of the
optionally substituted alkyl radicals, also mesyloxy, tosyloxy or
trifluoromethylsulphonyloxy or, in the case that R.sup.4-l represents a
carbonyl radical, the grouping --OR.sup.4-1.
The alkylating or acylating reagents of the formula (III) are generally
known reagents of organic chemistry and/or can be prepared by known
methods.
The formula (IV) provides a general definition of the aldehydes or ketones
required for carrying out the process (C) according to the invention. In
this formula, R.sup.5 and R.sup.6 each preferably represent those radicals
which have already been mentioned in connection with the description of
the oxadiazine derivatives of the formula (I) as being preferred
substituents.
Aldehydes and ketones of the formula (IV) are generally known and/or can be
prepared by known methods.
The oxadiazines of the formula (I-e) and (I-f) required for carrying out
the processes (D) and (E) according to the invention, respectively,
constitute sub-groups of the compounds of the formula (I) according to the
invention and can be prepared, for example, by processes (A) to (C) and
(F) to (H).
The formulae (V) and (VI) provide a general definition of the compounds
furthermore required for carrying out the processes (D) and (E). In these
formulae, R.sup.1-1 and R.sup.2-1 preferably represent those radicals
which have already been mentioned as being preferred for R.sup.1 and
R.sup.2, respectively, in connection with the description of the
oxadiazine derivatives of the formula (I), except for hydrogen, and E
correspondingly preferably represents the radicals mentioned in the
description of the compounds of the formula (III). Correspondingly means
that for carboxylic anhydrides of the formulae (V) and (VI) the groupings
--OR.sup.1-1 and --OR.sup.2-1, respectively, may replace --OR.sup.4-1.
The alkylating or acylating reagents of the formulae (V) and (VI) are
generally known reagents of organic chemistry and/or can be prepared by
known methods.
The formula (VII) provides a general definition of the compounds required
for carrying out the process (F) according to the invention. In this
formula, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and Q.sup.2 each preferably
represent those radicals which have already been mentioned in connection
with the description of the oxadiazine derivatives of the formula (I) as
being preferred substituents.
Compounds of the formula (VII) can be prepared, for example, by cleaving
the N-terminal protective group A.sup.3 of compounds of the formula
(XVIII) by customary methods, mentioned further above, according to the
following equation:
##STR39##
.alpha.-Hydroxy(thio)carbohydrazides of the formula (XVIII) can be
prepared, for example, by reacting .alpha.a-hydroxy(thio)carboxylic esters
of the formula (XIX) with hydrazines of the formula (XX) according to the
following equation:
##STR40##
In the formula (XIX), R.sup.7 represents optionally substituted alkyl or
aryl. The .alpha.-hydroxy(thio)carboxylates of the formula (XIX) are
commercially available or can be prepared, for example, from a-amino acids
via deamination (cf., for example, Tetrahedron Letters 28, 1873 (1987) and
26, 5257 (1985); Compr. Org. Chem. Vol. 2, 739-778 (1979); Ullmanns
Encyclopadie Techn. Chem. 4th edition (1977), Volume 13, 163).
Some hydrazines of the formula (XX) are known, or they can be obtained by
known methods (cf., for example, J. Chem. Soc. Perkin Trans. I 1975,
1712).
The formula (IX) provides a general definition of the compounds required
for carrying out the process (G) according to the invention. In this
formula, R.sup.1, R.sup.2, R.sup.3, R.sup.4, Q.sup.1 and Q.sup.2 each
preferably represent those radicals which have already been mentioned in
connection with the description of the oxadiazine derivatives of the
formula (1) as being preferred substituents. Y.sup.1 preferably represents
chlorine, trichloromethoxy, 1-imidazolyl, 1,2,4-triazolyl or Z-substituted
aryloxy, in particular pentafluorophenyl, 4-nitrophenyl or
2,4-dinitrophenyl.
Compounds of the formula (IX) can be prepared, for example, by cleaving the
N-terminal protective group A.sup.3 of compounds of the formula (XXI) by
methods mentioned further above according to the following equation:
##STR41##
Compounds of the formula (XXI) can be prepared, for example, by reacting
.alpha.-hydroxy(thio)carbohydrazides of the formula (XVIII) described
above with (thio)phosgenating reagents of the formula (VIII) described
further above and, if appropriate, reacting the resulting product of the
formula (XXI) in which Y.sup.1 does not yet represent Z-substituted
aryloxy with an appropriate phenol or phenolate such as, for example,
2,4-dinitrophenol.
The oxadiazines of the formula (I-a) required for carrying out the process
(H) according to the invention constitute sub-groups of the compounds of
the general formula (I) according to the invention and can be prepared,
for example, by processes (A) to (G).
The preferred thionylating reagents furthermore required for carrying out
the process (H) according to the invention are phosphorus pentasulphide or
2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetan-2,4-dithione
(Lawesson's reagent).
Suitable reaction auxiliaries for carrying out the process (A) according to
the invention are all compounds which are suitable for forming an amide
bond (cf., for example, Houben-Weyl, Methoden der Organischen Chemie,
Volume 15/2; Bodensky et al.; Peptide Synthesis 2nd ed., Wiley & Sons, New
York 1976). The following methods are preferred: activated ester method
using pentafluorophenol (PfP), N-hydroxysuccinimide,
1-hydroxybenzotriazole, coupling with carbodiimides such as
dicyclohexylcarbodiimide or N'-(3-dimethylaminopropyl)-N-ethylcarbodiimide
(EBC) and the mixed-anhydride-method or coupling with phosphonium reagents
such as 1-benzotriazolyloxy-tris-(dimethylaminophosphonium)
hexafluorophosphate (BOP), bis-(2-oxo-3-oxazolidinyl)-phosphoryl chloride
(BOP--Cl) or using phosphonic ester reagents such as diethyl
cyanophosphonate (DEPC) and diphenylphosphoryl azide (DPPA). Particular
preference is given to the coupling with
bis-(2-oxo-3-oxazolidinyl)-phosphoryl chloride (BOP--Cl) and
N'-(3-dimethylaminopropyl)-N-ethylcarbodiimide (EDC) in the presence of
1-hydroxybenzotriazole (HOBt).
Suitable diluents for carrying out the process (A) according to the
invention are organic solvents and any mixtures thereof. Examples include:
aliphatic, alicyclic or aromatic hydrocarbons, such as, for example,
petroleum ether, hexane, heptane, cyclohexane, methylcyclohexane, benzene,
toluene, xylene or decalin; halogenated hydrocarbons, such as, for
example, chlorobenzene, dichlorobenzene, methylene chloride, chloroform,
carbon tetrachloride, dichloro-, trichloroethane or tetrachloroethylene;
ethers, such as diethyl, diisopropyl, methyl t-butyl, methyl t-amyl ether,
dioxane, tetrahydrofuran, 1,2-dimethoxyethane, 1,2-diethoxyethane,
diethylene glycol dimethyl ether or anisole; ketones, such as acetone,
butanone, methyl isobutyl ketone or cyclohexanone; nitriles, such as
acetonitrile, propionitrile, n- or i-butyronitrile or benzonitrile;
amides, such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide,
N-methylformanilide, N-methylpyrrolidone,
1,3-dimethyl-tetrahydro-2-pyrimidinone (DMPU),
1,3-dimethyl-2-imidazolidinone, tetramethylurea or hexamethylphosphoric
triamide; N-oxides, such as N-methylmorpholine N-oxide; esters, such as
methyl, ethyl or butyl acetate; sulphoxides, such as dimethyl sulphoxide;
sulphones, such as sulpholane.
The cyclization is preferably carried out in the presence of a base.
Suitable bases are inorganic or organic bases. These preferably include
alkaline earth metal or alkali metal hydroxides, alkoxides, acetates,
carbonates or bicarbonates, such as, for example, sodium hydroxide,
potassium hydroxide or ammonium hydroxide, sodium methoxide, sodium
ethoxide, potassium tert-butoxide, sodium acetate, potassium acetate,
calcium acetate or ammonium acetate, sodium carbonate, potassium carbonate
or ammonium carbonate, sodium bicarbonate or potassium bicarbonate and
also tertiary amines, such as trimethylamine, triethylamine,
tributylamine, ethyl-diisopropylamine, N,N-dimethylaniline,
N,N-dimethyl-benzylamine, pyridine, picoline, N-methylpiperidine,
N-methylmorpholine, N,N-dimethylaminopyridine, diazabicyclooctane (DABCO),
diazabicyclononene (DBN) or diazabicycloundecene (DBU).
The reaction temperature in the process (A) according to the invention can
be varied within a relatively wide range. The cyclization is generally
carried out at temperatures between -40.degree. C. and +150.degree. C.,
preferably at -20.degree. C. to 100.degree. C., particularly preferably at
0.degree. C. to room temperature.
When carrying out the process (A) according to the invention, the compound
of the formula (JI) and the base are generally employed in a molar ratio
of 1:1 to 1:3, preferably 1:2.
The process (B) according to the invention can be carried out in the
presence of a diluent. Suitable diluents are water, organic solvents and
any mixtures thereof. Examples include: aliphatic, alicyclic or aromatic
hydrocarbons, such as, for example, petroleum ether, hexane, heptane,
cyclohexane, methylcyclohexane, benzene, toluene, xylene or decalin;
halogenated hydrocarbons, such as, for example, chlorobenzene,
dichlorobenzene, methylene chloride, chloroform, carbon tetrachloride,
dichloro-, trichloroethane or tetrachloroethylene; ethers, such as
diethyl, diisopropyl, methyl t-butyl, methyl t-amyl ether, dioxane,
tetrahydrofuran, 1,2-dimethoxyethane, 1,2-diethoxyethane, diethylene
glycol dimethyl ether or anisole; amides, such as formamide,
N,N-dimethylformamide, N,N-dimethylacetamide, N-methylformanilide,
N-methylpyrrolidone or hexamethylphosphoric triamide; N-oxides, such as
N-methylmorpholine N-oxide; esters, such as methyl, ethyl or butyl
acetate; sulphoxides, such as dimethyl sulphoxide; sulphones, such as
sulpholane; alcohols, such as methanol, ethanol, n- or i-propanol, n-,
iso-, sec- or tert-butanol, ethanediol, propane-1,2-diol, ethoxyethanol,
methoxyethanol, diethylene glycol monomethyl ether or diethylene glycol
monoethyl ether; water.
The process (B) according to the invention is preferably carried out in the
presence of a suitable reaction auxiliary. Suitable reaction auxiliaries
are all customary inorganic or organic bases. These preferably include
alkaline earth metal or alkali metal hydrides, hydroxides, alkoxides,
amides, acetates, carbonates or bicarbonates, such as, for example, sodium
hydride, sodium hydroxide, potassium hydroxide or ammonium hydroxide,
sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium amide,
lithium diisopropylamide, lithium bis(trimethylsilyl) amide, sodium
bis(trimethylsilyl) amide, potassium bis(trimethylsilyl) amide, sodium
acetate, potassium acetate, calcium acetate or ammonium acetate, sodium
carbonate, potassium carbonate or ammonium carbonate, sodium bicarbonate
or potassium bicarbonate; lithium alkyls such as methyl-, n-butyl-,
sec-butyl- or tert-butyllithium and also tertiary amines, such as
trimethylamine, triethylamine, tributylamine, N,N-dimethylaniline,
N,N-dimethyl-benzylamine, pyridine, N-methylpiperidine,
N-methylmorpholine, N,N-dimethylaminopyridine, diazabicyclooctane (DABCO),
diazabicyclononene (DBN) or diazabicycloundecene (DBU).
The reaction temperature in the process (B) according to the invention can
be varied within a relatively wide range. In general, the reaction is
carried out at temperatures between -100.degree. C. and +150.degree. C.,
preferably between -78.degree. C. and 100.degree. C.
When carrying out the process (B) according to the invention, the
oxadiazine derivative of the formula (I-c), the reagent of the formula
(III) and the base are generally employed in each case in approximately
equimolar amounts. However, it is also possible to employ a relatively
large excess (up to 50 mol) of reagent and base.
The process (C) according to the invention can be carried out in the
presence of a diluent. Suitable diluents are preferably those listed for
process (B).
The process (C) according to the invention is preferably carried out in the
presence of a suitable reaction auxiliary. Suitable reaction auxiliaries
are preferably all bases listed for process (B).
The reaction temperature in the process (C) according to the invention can
be varied within a relatively wide range. In general, the reaction is
carried out at temperatures between -100.degree. C. and +120.degree. C.,
preferably between -78.degree. C. and 100.degree. C.
To eliminate water, if this does not take place without assistance, an acid
may be used. Suitable acids are all inorganic and organic protic and also
Lewis acids, and also all polymeric acids. These include, for example,
hydrogen chloride, sulphuric acid, phosphoric acid, formic acid, acetic
acid, trifluoroacetic acid, methanesulphonic acid,
trifluoromethanesulphonic acid, toluenesulphonic acid, boron trifluoride
(also as etherate), boron tribromide, aluminium trichloride, zinc
chloride, iron(III) chloride, antimony pentachloride, acidic ion
exchangers, acidic aluminas and acidic silica gel.
When carrying out process (C) according to the invention, the oxadiazine
derivative of the formula (I-c), the carbonyl compound of the formula (IV)
and the base are generally in each case employed in approximately
equimolar amounts. However, it is also possible to employ a relatively
large excess (up to 50 mol) of reagent and base.
The processes (D) and (E) according to the invention can be carried out in
the presence of a diluent. Preferred diluents are the diluents listed for
process (B).
The processes (D) and (E) according to the invention are preferably carried
out in the presence of a suitable reaction auxiliary. Suitable reaction
auxiliaries are all bases listed for process (B). Additionally, they also
include catalysts such as, for example, 4-(N,N-dimethylamino)-pyridine.
The reaction temperatures in the processes (D) and (E) according to the
invention can be varied within a relatively wide range. In general, the
reaction is carried out at temperatures between -40.degree. C. and
+120.degree. C., preferably between -10.degree. C. and 100.degree. C.
When carrying out the processes (D) and (E) according to the invention, the
oxadiazine derivative of the formula (I-g) or (I-h), the compound of the
formula (V) or (VI) and the base are generally in each case employed in
approximately equimolar amounts. However, it is also possible to employ a
relatively large excess (up to 50 mol) of reagent and base. If
appropriate, amounts of catalyst of 0.001 to 0.1 mole per mol of
oxadiazine derivative are employed.
The process (F) according to the invention can be carried out in the
presence of a diluent. Preferred diluents are the diluents listed for
process (A).
The process (F) according to the invention can be carried out in the
presence of a suitable reaction auxiliary. Suitable reaction auxiliaries
are all bases listed for process (A).
The reaction temperature in the process (F) according to the invention can
be varied within a relatively wide range. In general, the reaction is
carried out at temperatures between -20.degree. C. and +150.degree. C.,
preferably between +20.degree. C. and 120.degree. C., the cyclization
optionally being initiated by an increase in temperature after the
reaction of the two reactants.
When carrying out the process (F) according to the invention, 1.0 to 2.0
mol, preferably 1.0 to 1.2 mol of the compound (VIII) and optionally 1.0
to 5 mol of reaction auxiliary are employed per mole of the compound of
the formula (VII).
The process (G) according to the invention can be carried out in the
presence of a diluent. Preferred diluents are the diluents listed in
process (A).
The process (G) according to the invention can be carried out in the
presence of a suitable reaction auxiliary. Suitable reaction auxiliaries
are all bases listed in process (A).
The reaction temperature in the process (G) according to the invention can
be varied within a relatively wide range. In general, the reaction is
carried out at temperatures between 20.degree. C. and +150.degree. C.,
preferably between +20.degree. C. and 120.degree. C.
When carrying out the process (G) according to the invention, the compound
of the formula (II) and the base are generally employed in a molar ratio
of 1:1 to 1:3, preferably in equimolar amounts.
The process (H) according to the invention can be carried out in the
presence of a diluent. Suitable diluents are organic solvents and any
mixtures thereof. Examples include: aliphatic, alicyclic or aromatic
hydrocarbons, such as, for example, petroleum ether, hexane, heptane,
cyclohexane, methylcyclohexane, benzene, toluene, xylene or decalin;
halogenated hydrocarbons, such as, for example, chlorobenzene,
dichlorobenzene, methylene chloride, chloroform, carbon tetrachloride,
dichloro-, trichloroethane or tetrachloroethylene; ethers, such as
diethyl, diisopropyl, methyl t-butyl, methyl t-amyl ether, dioxane,
tetrahydrofuran, 1,2-dimethoxyethane, 1,2-diethoxyethane, diethylene
glycol dimethyl ether or anisole; ureas, such as
1,3-dimethyl-tetrahydro-2-pyrimidinone (DMPU),
1,3-dimethyl-2-imidazolidinone, tetramethylurea; hexamethylphosphoric
triamide; sulphoxides, such as dimethyl sulphoxide; sulphones, such as
sulpholane.
The reaction temperature in the process (H) according to the invention can
be varied within a relatively wide range. In general, the reaction is
carried out at temperatures between 0.degree. C. and +150.degree. C.,
preferably between +20.degree. C. and 100.degree. C.
When carrying out the process (H) according to the invention, in general 1
to 20, preferably 1 to 5 mol of sulphurizing reagent are employed per mole
of the compound of the formula (I-a).
The reactions of the processes according to the invention can be carried
out at atmospheric pressure or under elevated pressure and are preferably
carried out at atmospheric pressure. Work-up is carried out by customary
methods of organic chemistry. The end products are preferably purified by
crystallization, chromatographic purification or by removing the volatile
components, if appropriate under reduced pressure.
The active compounds are suitable for controlling pathogenic endoparasites
encountered in humans and in animal husbandry and livestock breeding, in
productive livestock, breeding stock, zoo animals, laboratory animals,
animals used in experiments, and pets, and have low toxicity towards
warm-blooded animals. They are active against resistant and normally
sensitive species and against all or some stages of development of the
pests. By controlling the pathogenic endoparasites, it is intended to
reduce disease, mortality and decreasing performance (for example in the
production of meat, milk, wool, hides, eggs, honey, etc.), so that more
economical and simpler animal keeping is possible by using the active
compounds. The pathogenic endoparasites include cestodes, trematodes,
nematodes, in particular:
From the order of the Pseudophyllidea, for example Diphyllobothrium spp.,
Spirometra spp., Schistocephalus spp., Ligula spp., Bothridium spp.,
Diphlogonoorus spp.
From the order of the Cyclophyllidea, for example Mesocestoides spp.,
Anoplocephala spp., Paranoplocephala spp., Moniezia spp., Thysanosmsa
spp., Thysaniezia spp., Avitellina spp., Stilesia spp., Cittotaenia spp.,
Anhyra spp., Bertielua spp., Taenia spp., Echinococcus spp., Fydratigera
spp., Davainea spp., Raillietina spp., Hymenolepsis spp., Echinolepsis
spp., Echinocotyle spp., Diorchis spp., Dipylidium spp., Joyeuxielia spp.,
Diplopylidium spp.
From the subclass of the Monogenea, for example Cyrodactylus spp.,
Dactylogyrus spp., Polystoma spp.
From the subclass of the Digenea, for example Diplostomum spp.,
Posthodiplostomum spp., Schistosoma spp., Trichobilharzia spp.,
Opithobilharzia spp., Austrobilharzia spp., Gigantobilharzia spp.,
Leucochloridium spp., Brachylaima spp., Echinostoma spp., Echinoparyphium
spp., Echinochasmus spp., Hypoderaeum spp., Fasciola spp., Fasciolides
spp., Fasciolopsis spp., Cyclocoelum spp., Typhloccelum spp.,
Paramphistomum spp., Calicophoron spp, Cotylophoron spp., Gigantocotyle
spp., Fischoederius spp., Gastrothylacus spp., Notocotylus spp.,
Catatropis spp., Plagiorchis spp., Prosthogonismus spp., Dicrocoelium
spp., Collyriclum spp., Nanophyetus spp., Opisthorchis spp., Clonorchis
spp., Metorchis spp., Heterophyes spp., Metagonimus From the order of the
Enopyida, for example Trichuris spp., Capillaria spp., Trichromosoides
spp., Trichinella spp.
From the order of the Rhabditia, for example Micronema spp., Strongyloides
spp.
From the order of the Strongylida, for example Stronylus spp.,
Triodontophorus spp., Oesophagodontus spp., Trichonema spp., Gyalocephalus
spp., Cylindropharynx spp., Poteriostomum spp., Cyclococercus spp.,
Cylicostephanus spp., Oesophagostomum spp., Chabertia spp., Stephanurus
spp., Acylostoma spp., Uncinaria spp., Bunostomum spp., Globocephalus
spp., Syngamus spp., Cyathostoma spp., Metastrongylus spp., Dictyocaulus
spp., Muellerius spp., Protostrongylus spp., Neostrongylus spp.,
Cystocaulus spp., Pneumostrongylus spp., Spicocaulus spp.,
Elaphostrongylus spp., Parelaphostrongylus spp., Crenosoma spp.,
Paracrenosoma spp., Angiostrongylus spp., Aelurostrongylus spp.,
Filaroides spp., Parafilaroides spp., Trichostrongylus spp., Haemonchus
spp., Ostertagia spp., Marshallagia spp., Cooperia spp., Nematodirus spp.,
Hyostrongylus spp., Obeliscoides spp., Amidostomum spp., Ollulanus spp.
From the order of the Oxyurida, for example Oxyuris spp., Enterobius spp.,
Passalurus spp., Syphacia spp., Aspiculuris spp., Heterakis spp.
From the order of the Ascaridia, for example Ascaris spp., Toxascaris spp.,
Toxocara spp., Parascaris spp., Anisakis spp., Ascaridia spp.
From the order of the Spirurida, for example Gnathostoma spp., Physaloptera
spp., Thelazia spp., Gongylonema spp., Habronema spp., Parabronema spp.,
Draschia spp., Dracunculus spp.
From the order of the Filariida, for example Stephanofilaria spp.,
Parafilaria spp., Setaria spp., Loa spp., Dirofilaria spp., Litomosoides
spp., Brugia spp., Wuchereria spp., Onchocerca spp.
From the group of the Gigantohynchida, for example Filicollis spp.,
Moniliformis spp., Macracanthorhynchus spp., Prosthenorchis spp.
For example, they have outstanding activity against nematodes such as
Haemonchus contortus.
The livestock and breeding stock include mammals, such as, for example,
cattle, horses, sheep, pigs, goats, camels, water buffalo, donkeys,
rabbits, fallow deer, reindeer, fur-bearing animals, such as, for example,
minks, chinchilla or racoons, birds, such as, for example, chickens,
geese, turkeys or ducks, freshwater fish and sea fish, such as, for
example, trout, carp and eels, reptiles and insects, such as, for example,
honey bee and silkworm.
The laboratory and test animals include mice, rats, guinea pigs, golden
hamsters, dogs and cats.
The pets include dogs and cats.
Administration can be effected prophylactically as well as therapeutically.
The active substances are administered, either directly or in the form of
suitable preparations, enterally, parenterally, dermally, nasally, by
treating the habitat or with the aid of shaped articles containing the
active compound, such as, for example, strips, plates, tapes, collars, ear
tags, limb bands or marking devices.
Enteral administration of the active compounds is effected for example
orally in the form of powders, suppositories, tablets, capsules, pastes,
drinks, granules, solutions, suspensions and emulsions which can be
applied orally, boluses, medicated feed or drinking water. Dermal
application is effected, for example, in the form of dipping, spraying,
bathing, washing, or pouring-on and spotting-on, and powdering. Parenteral
administration is effected, for example, in the form of injection
(intramuscular, subcutaneous, intravenous or intraperitoneal) or by
implants.
Suitable preparations include:
Solutions, such as solutions for injection, oral solutions, concentrates
for oral administration after dilution, solutions for use on the skin or
in body cavities, pour-on formulations, gels;
Emulsions and suspensions for oral or dermal administration and for
injection; semi-solid preparations;
Formulations in which the active compound is incorporated in a cream base
or in an oil-in-water or water-in-oil emulsion base;
Solid preparations, such as powders, premixes or concentrates, granules,
pellets, tablets, boluses, capsules; aerosols and inhalants, shaped
articles containing the active compound.
Solutions for injection are administered intravenously, intramuscularly and
subcutaneously.
Solutions for injection are prepared by dissolving the active compound in a
suitable solvent and, if desired, adding additives, such as solubilizers,
acids, bases, buffer salts, antioxidants, or preservatives. The solutions
are sterile-filtered and decanted into containers.
Suitable solvents include: physiologically acceptable solvents, such as
water, alcohols, such as ethanol, butanol, benzyl alcohol, glycerol,
hydrocarbons, propylene glycol, polyethylene glycols and
N-methylpyrrolidone, and their mixtures.
If appropriate, the active compounds can also be dissolved in
physiologically acceptable vegetable or synthetic oils which are suitable
for injection.
Suitable solubilizers include: solvents which facilitate the dissolution of
the active compound in the main solvent or which prevent precipitation of
the active compound. Examples of solubilizers are polyvinylpyrrolidone,
polyethoxylated castor oil and polyethoxylated sorbitan esters.
The following are preservatives: benzyl alcohol, trichlorobutanol,
p-hydroxybenzoic esters or n-butanol.
Oral solutions are administered directly. Concentrates are first diluted to
the administration concentration and then administered orally. Oral
solutions and concentrates are prepared as described above in the case of
the solutions for injection, sterile procedures not being necessary.
Solutions for use on the skin are applied drop by drop, smoothed on, rubbed
in, splashed on or sprayed on, or applied by dipping, bathing or washing.
These solutions are prepared as described above in the case of the
solutions for injection.
It may be advantageous to add thickeners in the preparation process. The
following are thickeners: inorganic thickeners, such as bentonites,
colloidal silica, aluminium monostearate, or organic thickeners, such as
cellulose derivatives, polyvinyl alcohols and their copolymers, acrylates
and methacrylates.
Gels are applied to the skin or smoothed on or introduced into body
cavities. Gels are prepared by adding such an amount of thickener to
solutions which have been prepared as described for the solutions for
injection that a clear composition is formed which has an ointment-like
consistency. The thickeners used are the thickeners indicated further
above.
Pour-on and spot-on formulations are poured or splashed onto limited areas
of the skin, the active compound penetrating the skin and acting
systemically, or spreading on the body surface.
Pour-on and spot-on formulations are prepared by dissolving, suspending or
emulsifying the active compound in suitable solvents or solvent mixtures
which are tolerated by the skin. If appropriate, other auxiliaries, such
as colorants, absorption promoters, antioxidants, photostabilizers or
tackifiers are added.
Suitable solvents include: water, alkanols, glycols, polyethylene glycols,
polypropylene glycols, glycerol, aromatic alcohols, such as benzyl
alcohol, phenylethanol or phenoxyethanol, esters, such as ethyl acetate,
butyl acetate or benzyl benzoate, ethers, such as alkylene glycol alkyl
ethers, such as dipropylene glycol monomethyl ether or diethylene glycol
mono-butyl ether, ketones, such as acetone or methyl ethyl ketone,
aromatic and/or aliphatic hydrocarbons, vegetable or synthetic oils, DMF,
dimethyl-acetamide, N-methylpyrrolidone,
2,2-dimethyl-4-oxy-methylene-1,3-dioxolane.
Colorants are all colorants which can be dissolved or suspended and which
are approved for use in animals.
Examples of absorption promoters are DMSO, spreading oils, such as
isopropyl myristate, dipropylene glycol pelargonate, silicone oils, fatty
acid esters, triglycerides or fatty alcohols.
The following are antioxidants: sulphites or metabisulphites, such as
potassium metabisulphate, ascorbic acid, butylhydroxytoluene,
butylhydroxyanisole or tocopherol.
Example of photostabilizers are compounds from the class of the
benzophenones or novantisolic acid.
Tackifiers are, for example, cellulose derivatives, starch derivatives,
polyacrylates or natural polymers such as alginates or gelatin.
Emulsions can be administered orally, dermally or as injections.
Emulsions are either the water-in-oil type or the oil-in-water type.
They are prepared by dissolving the active compound either in the
hydrophobic or in the hydrophilic phase and by homogenizing this phase
with the solvent of the other phase, with the aid of suitable emulsifiers
and, if appropriate, other auxiliaries, such as colorants, absorption
promoters, preservatives, antioxidants, photostabilizers, and
viscosity-increasing substances.
Suitable hydrophobic phases (oils) include: paraffin oils, silicone oils,
natural vegetable oils such as sesame seed oil, almond oil or castor oil,
synthetic triglycerides, such as caprylic/capric acid biglyceride, a
triglyceride mixture with vegetable fatty acids of chain length C.sub.8-12
or other specifically selected natural fatty acids, mixtures of partial
glycerides of saturated or unsaturated fatty acids which may also contain
hydroxyl groups, and mono- and diglycerides of the C.sub.8 /C.sub.10
-fatty acids.
Fatty acid esters, such as ethyl stearate, di-n-butyryl adipate, hexyl
laurate, dipropylene glycol pelargonate, esters of a branched fatty acid
having a medium chain length with saturated fatty alcohols of chain length
C.sub.16 -C.sub.18, isopropyl myristate, isopropyl palmitate,
caprylic/capric esters of saturated fatty alcohols of chain length
C.sub.12 -C.sub.18, isopropyl stearate, oleyl oleate, decyl oleate, ethyl
oleate, ethyl lactate, waxy fatty acid esters such as artificial duck
uropygial fat, dibutyl phthalate, diisopropyl adipate, ester mixtures
related to the latter, etc.
Fatty alcohols, such as isotridecyl alcohol, 2-octyldodecanol, cetylstearyl
alcohol or oleyl alcohol.
Fatty acids, such as, for example, oleic acid and its mixtures.
Suitable hydrophilic phases include:
water, alcohols, such as, for example, propylene glycol, glycerol, sorbitol
and their mixtures.
Suitable emulsifiers include: nonionic surfactants, for example
polyethoxylated castor oil, polyethoxylated sorbitan monooleate, sorbitan
monostearate, glycerol monostearate, polyoxyethyl stearate or alkylphenol
polyglycol ethers;
ampholytic surfactants, such as disodium N-lauryl-.beta.-iminodipropionate
or lecithin;
anionic surfactants, such as Na lauryl sulfate, fatty alcohol ether
sulfates, and the monoethanolamine salt of mono/dialkylpolyglycol ether
orthophosphoric ester;
cationic surfactants, such as cetyltrimethylammonium chloride.
Suitable other auxiliaries include: substances which increase the viscosity
and stabilize the emulsion, such as carboxymethylcellulose,
methylcellulose and other cellulose and starch derivatives, polyacrylates,
alginates, gelatin, gum arabic, polyvinyl-pyrrolidone, polyvinyl alcohol,
methylvinyl ether/maleic anhydride copolymers, polyethylene glycols,
waxes, colloidal silica, or mixtures of the listed substances.
Suspensions can be administered orally, dermally or as an injection. They
are prepared by suspending the active compound in a liquid excipient, if
appropriate with the addition of other auxiliaries, such as wetting
agents, colorants, absorption promoters, preservatives, antioxidants and
photostabilizers.
Suitable liquid excipients include all homogeneous solvents and solvent
mixtures.
Suitable wetting agents (dispersants) include the surfactants indicated
further above.
Suitable other auxiliaries include those indicated further above.
Semi-solid preparations can be administered orally or dermally. They are
only distinguished from the above-described suspensions and emulsions by
their higher viscosity.
To prepare solid preparations, the active compound is mixed with suitable
excipients, if appropriate with the addition of auxiliaries, and the
mixture is formulated as desired.
Suitable excipients include all physiologically acceptable solid inert
substances. Suitable for this purpose are inorganic and organic
substances. Inorganic substances are, for example, common salt,
carbonates, such as calcium carbonate, hydrogen carbonates, aluminium
oxides, silicas, clays, precipitated or colloidal silica, and phosphates.
Organic substances are, for example, sugars, cellulose, foodstuffs and
animal feeds, such as powdered milk, animal meals, cereal meals, coarse
cereal meals and starches.
Auxiliaries are preservatives, antioxidants and colorants which have
already been mentioned further above.
Other suitable auxiliaries are lubricants and glidants, such as, for
example, magnesium stearate, stearic acid, talc, bentonites,
disintegrants, such as starch or crosslinked polyvinylpyrrolidone,
binders, such as, for example, starch, gelatin or linear
polyvinylpyrrolidone, and dry binders, such as microcrystalline cellulose.
In the preparations, the active compounds can also be present in mixtures
with synergists or other active compounds which are active against
pathogenic endoparasites. Examples of such active compounds are
L-2,3,5,6-tetrahydro-6-phenyl-imidazolylthiazole, benzimidazole
carbamates, praziquantel, pyrantel or febantel.
Ready-to-use preparations contain the active compound in concentrations of
10 ppm to 20 percent by weight, preferably from 0.1 to 10 percent by
weight.
Preparations which are diluted before use contain the active compound in
concentrations of 0.5 to 90 percent by weight, preferably from 5 to 50
percent by weight.
In general, it has proven advantageous to administer amounts of about 1 to
100 mg of active compound per kg of body weight per day to obtain
effective results.
The active compounds are furthermore suitable for controlling animal pests,
in particular insects, arachnids and nematodes, encountered in
agriculture, in forestry, in the protection of stored products and of
materials, and in the hygiene field, and have good plant tolerance and low
toxicity to warm-blooded animals. They are active against normally
sensitive and resistant species and against all or some stages of
development. The abovementioned pests include:
From the order of the Isopoda, for example, Oniscus asellus, Armadillidium
vulgare and Porcellio scaber.
From the order of the Diplopoda, for example, Blaniulus guttulatus.
From the order of the Chilopoda, for example, Geophilus carpophagus and
Scutigera spec.
From the order of the Symphyla, for example, Scutigerella immaculata.
From the order of the Thysanura, for example, Lepisma saccharina.
From the order of the Collembola, for example, Onychiurus armatus.
From the order of the Orthoptera, for example, Blatta orientalis,
Periplaneta americana, Leucophaea maderae, Blattella germanica, Acheta
domesticus, Gryllotalpa spp., Locusta migratoria migratorioides,
Melanoplus differentialis and Schistocerca gregaria.
From the order of the Dermaptera, for example, Forficula auricularia.
From the order of the Isoptera, for example, Reticulitermes spp.
From the order of the Anoplura, for example, Pediculus humanus corporis,
Haematopinus spp. and Linognathus spp.
From the order of the Mallophaga, for example, Trichodectes spp. and
Damalinea spp.
From the order of the Thysanoptera, for example, Hercinothrips femoralis
and Thrips tabaci.
From the order of the Heteroptera, for example, Eurygaster spp., Dysdercus
intermedius, Piesma quadrata, Cimex lectularius, Rhodnius prolixus and
Triatoma spp.
From the order of the Homoptera, for example, Aleurodes brassicae, Bemisia
tabaci, Trialeurodes vaporariorum, Aphis gossypii, Brevicoryne brassicae,
Cryptomyzus ribis, Aphis fabae, Aphis pomi, Eriosoma lanigerum,
Hyalopterus arundinis, Phylloxera vastatrix, Pemphigus spp., Macrosiphum
avenae, Myzus spp., Phorodon humuli, Rhopalosiphum padi, Empoasca spp.,
Euscelis bilobatus, Nephotettix cincticeps, Lecanium corni, Saissetia
oleae, Laodelphax striatellus, Nilaparvata lugens, Aonidiella aurantii,
Aspidiotus hederae, Pseudococcus spp. Psylla spp.
From the order of the Lepidoptera, for example, Pectinophora gossypiella,
Bupalus piniarius, Cheimatobia brumata, Lithocolletis blancardella,
Hyponomeuta padella, Plutella maculipennis, Malacosoma neustria, Euproctis
chrysorrhoea, Lymantria spp., Bucculatrix thurberiella, Phyllocnistis
citrella, Agrotis spp., Euxoa spp., Feltia spp., Earias insulana,
Heliothis spp., Laphygma exigua, Mamestra brassicae, Panolis flammea,
Prodenia litura, Spodoptera spp., Trichoplusia ni, Carpocapsa pomonella,
Pieris spp., Chilo spp., Pyrausta nubilalis, Ephestia kuehniella, Galleria
mellonella, Tineola bisselliella, Tinea pellionella, Hofmannophila
pseudospretella, Cacoecia podana, Capua reticulana, Choristoneura
fumiferana, Clysia ambiguella, Homona magnanima and Tortrix viridana.
From the order of the Coleoptera, for example, Anobium punctatum,
Rhizopertha dominica, Bruchidius obtectus, Acanthoscelides obtectus,
Hylotrupes bajulus, Agelastica alni, Leptinotarsa decemlineata, Phaedon
cochleariae, Diabrotica spp., Psylliodes chrysocephala, Epilachna
varivestis, Atomaria spp., Oryzaephilus surinamensis, Anthonomus spp.,
Sitophilus spp., Otiorrhynchus sulcatus, Cosmopolites sordidus,
Ceuthorrhynchus assimilis, Hypera postica, Dermestes spp., Trogoderma
spp., Anthrenus spp., Attagenus spp., Lyctus spp., Meligethes aeneus,
Ptinus spp., Niptus hololeucus, Gibbium psylloides, Tribolium spp.,
Tenebrio molitor, Agriotes spp., Conoderus spp., Melolontha melolontha,
Amphimallon solstitialis and Costelytra zealandica.
From the order of the Hymenoptera, for example, Diprion spp., Hoplocampa
spp., Lasius spp., Monomorium pharaonis and Vespa spp.
From the order of the Diptera, for example, Aedes spp., Anopheles spp.,
Culex spp., Drosophila melanogaster, Musca spp., Fannia spp., Calliphora
erythrocephala, Lucilia spp., Chrysomyia spp., Cuterebra spp.,
Gastrophilus spp., Hyppobosca spp., Stomoxys spp., Oestrus spp., Hypoderma
spp., Tabanus spp., Tannia spp., Bibio hortulanus, Oscinella frit, Phorbia
spp., Pegomyia hyoscyami, Ceratitis capitata, Dacus oleae and Tipula
paludosa.
From the order of the Siphonaptera, for example, Xenopsylla cheopis and
Ceratophyllus spp.
From the order of the Arachnida, for example, Scorpio maurus, Latrodectus
mactans.
From the order of the Acarina, for example, Acarus siro, Argas spp.,
Ornithodoros spp., Dermanyssus gallinae, Eriophyes ribis, Phyllocoptruta
oleivora, Boophilus spp., Rhipicephalus spp., Amblyomma spp., Hyalomma
spp., Ixodes spp., Psoroptes spp., Chorioptes spp., Sarcoptes spp.,
Tarsonemus spp., Bryobia praetiosa, Panonychus spp., Tetranychus spp.
The phytoparasitic nematodes include Pratylenchus spp., Radopholus similis,
Ditylenchus dipsaci, Tylenchulus semipenetrans, Heterodera spp.,
Meloidogyne spp., Aphelenchoides spp., Longidorus spp., Xiphinema spp.,
Trichodorus spp.
The active compounds according to the invention in particular have
outstanding activity against the caterpillars of the diamond-back moth
(Plutella maculipennis).
The active compounds can be converted to the customary formulations, such
as solutions, emulsions, wettable powders, suspensions, powders, dusting
agents, pastes, soluble powders, granules, suspension emulsion
concentrates, natural and synthetic materials impregnated with active
compound and very fine capsules in polymeric substances.
These formulations are produced in a known manner, for example by mixing
the active compounds with extenders, that is liquid solvents and/or solid
carriers, if appropriate with the use of surfactants, that is emulsifiers
and/or dispersing agents and/or foam-forming agents.
If the extender used is water, it is also possible to employ, for example,
organic solvents as auxiliary solvents. Suitable liquid solvents are
essentially: aromatics, such as xylene, toluene or alkylnaphthalenes,
chlorinated aromatics or chlorinated aliphatic hydrocarbons, such as
chlorobenzenes, chloroethylenes or methylene chloride, aliphatic
hydrocarbons, such as cyclohexane or paraffins, for example mineral oil
fractions, mineral and vegetable oils, alcohols, such as butanol or glycol
and also their ethers and esters, ketones, such as acetone, methyl ethyl
ketone, methyl isobutyl ketone or cyclohexanone, strongly polar solvents,
such as dimethylformamide and dimethyl sulphoxide, and also water.
Suitable solid carriers are:
for example ammonium salts and ground natural minerals, such as kaolins,
clays, talc, chalk, quartz, attapulgite, montmorillonite or diatomaceous
earth, and ground synthetic minerals, such as highly disperse silica,
alumina and silicates; suitable solid carriers for granules are: for
example crushed and fractionated natural rocks such as calcite, marble,
pumice, sepiolite and dolomite, and also synthetic granules of inorganic
and organic meals, and granules of organic material such as sawdust,
coconut shells, maize cobs and tobacco stalks; suitable emulsifying and/or
foam-forming agents are: for example non-ionic and anionic emulsifiers,
such as polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol
ethers, for example alkylaryl polyglycol ethers, alkylsulphonates, alkyl
sulphates, arylsulphonates and also protein hydrolysis products; suitable
dispersing agents are: for example lignin-sulphite waste liquors and
methylcellulose.
Tackifiers such as carboxymethylcellulose and natural and synthetic
polymers in the form of powders, granules or latices, such as gum arabic,
polyvinyl alcohol and polyvinyl acetate, and also natural phospholipids,
such as cephalins and lecithins, and synthetic phospholipids, can be used
in the formulations. Other possible additives are mineral and vegetable
oils.
It is possible to use colorants such as inorganic pigments, for example
iron oxide, titanium oxide and Prussian Blue, and organic dyestuffs, such
as alizarin dyestuffs, azo dyestuffs and metal phthalocyanine dyestuffs,
and trace nutrients such as salts of iron, manganese, boron, copper,
cobalt, molybdenum and zinc.
The formulations in general contain between 0.1 and 95 per cent by weight
of active compound, preferably between 0.5 and 90%.
The active compound according to the invention can be present in its
commercially available formulations and in the use forms, prepared from
these formulations, as a mixture with other active compounds, such as
insecticides, attractants, sterilizing agents, acaricides, nematicides,
fungicides, growth-regulating substances or herbicides. The insecticides
include, for example, phosphates, carbamates, carboxylates, chlorinated
hydrocarbons, phenylureas and substances produced by microorganisms, inter
alia.
Examples of particularly advantageous mixing components are the following:
Fungicides:
2-aminobutane; 2-anilino-4-methyl-6-cyclopropyl-pyrimidine;
2',6'-dibromo-2-methyl-4'-trifluoromethoxy-4'-trifluoro-methyl-1,3-thiazol
e-5-carboxanilide; 2,6-dichloro-N-(4-trifluoromethylbenzyl)-benzamide;
(E)-2-methoxyimino-N-methyl-2-(2-phenoxyphenyl)-acetamide;
8-hydroxyquinoline sulphate; methyl
(E)-2-{2-[6-(2-cyanophenoxy)-pyrimidin-4-yloxy]-phenyl}-3-methoxyacrylate;
methyl (E)-methoximino[alpha-(o-tolyloxy)-o-tolyl]acetate; 2-phenylphenol
(OPP), aldimorph, ampropylfos, anilazine, azaconazole,
benalaxyl, benodanil, benomyl, binapacryl, biphenyl, bitertanol,
blasticidin-S, bromuconazole, bupirimate, buthiobate,
calcium polysulphide, captafol, captan, carbendazim, carboxin,
quinomethionate, chloroneb, chloropicrin, chlorothalonil, chlozolinate,
cufraneb, cymoxanil, cyproconazole, cyprofuram,
dichlorophen, diclobutrazol, diclofluanid, diclomezine, dicloran,
diethofencarb, difenoconazole, dimethirimol, dimethomorph, diniconazole,
dinocap, diphenylamine, dipyrithione, ditalimfos, dithianon, dodine,
drazoxolon,
edifenphos, epoxyconazole, ethirimol, etridiazole,
fenarimol, fenbuconazole, fenfuram, fenitropan, fenpiclonil, fenpropidin,
fenpropimorph, fentin acetate, fentin hydroxide, ferbam, ferimzone,
fluazinam, fludioxonil, fluoromide, fluquinconazole, flusilazole,
flusulfamide, flutolanil, flutriafol, folpet, fosetyl-aluminium, fhalide,
fuberidazole, furalaxyl, furmecyclox,
guazatine,
hexachlorobenzene, hexaconazole, hymexazol,
imazalil, imibenconazole, iminoctadine, iprobenfos (IBP), iprodione,
isoprothiolane, kasugamycin, copper preparations such as: copper
hydroxide, copper naphthenate, copper oxychloride, copper sulphate, copper
oxide, oxine-copper and Bordeaux mixture, mancopper, mancozeb, maneb,
mepanipyrim, mepronil, metalaxyl, metconazole, methasulfocarb,
methfuroxam, metiram, metsulfovax, myclobutanil,
nickel dimethyldithiocarbamate, nitrothal-isopropyl, nuarimol,
ofurace, oxadixyl, oxamocarb, oxycarboxin,
pefurazoate, penconazole, pencycuron, phosdiphen, phthalide, pimaricin,
piperalin, polycarbamate, polyoxin, probenazole, prochloraz, procymidone,
propamocarb, propiconazole, propineb, pyrazophos, pyrifenox, pyrimethanil,
pyroquilon,
quintozene (PCNB),
sulphur and sulphur preparations,
tebuconazole, tecloftalam, tecnazene, tetraconazole, thiabendazole,
thicyofen, thiophanate-methyl, thiram, tolclophos-methyl, tolylfluanid,
triadimefon, triadimenol, triazoxide, trichlamide, tricyclazole,
tridemorph, triflumizole, triforine, triticonazole,
validamycin A, vinclozolin,
zineb, ziram.
Bactencides:
bronopol, dichlorophen, nitrapyrin, nickel dimethyldithiocarbamate,
kasugamycin, octhilinone, furancarboxylic acid, oxytetracycline,
probenazole, streptomycin, tecloftalam, copper sulphate and other copper
preparations.
Insecticides/Acaricides/Nematicides:
abamectin, AC303 630, acephate, acrinathrin, alanycarb, aldicarb,
alphamethrin, amitraz, avermectin, AZ 60541, azadirachtin, azinphos A,
azinphos M, azocyclotin, Bacillus thuringiensis, bendiocarb, benfuracarb,
bensultap, beta-cyfluthrin, bifenthrin, BPMC, brofenprox, bromophos A,
bufencarb, buprofezin, butocarboxin, butylpyridaben, cadusafos, carbaryl,
carbofuran, carbophenothion, carbosulfan, cartap, CGA 157419, CGA 184699,
chloethocarb, chlorethoxyfos, chlorfenvinphos, chlorfluazuron,
chlormephos, chlorpyrifos, chlorpyrifos M, cis-resmethrin, clocythrin,
clofentezine, cyanophos, cycloprothrin, cyfluthrin, cyhalothrin,
cyhexatin, cypermethrin, cyromazine, deltamethrin, demeton M, demeton S,
demeton--S--methyl, diafenthiuron, diazinon, dichlofenthion, dichlorvos,
dicliphos, dicrotophos, diethion, diflubenzuron, dimethoate,
dimethylvinphos, dioxathion, disulfoton,
edifenphos, emamectin, esfenvalerate, ethiofencarb, ethion, ethofenprox,
ethoprophos, etrimphos,
fenamiphos, fenazaquin, fenbutatin oxide, fenitrothion, fenobucarb,
fenothiocarb, fenoxycarb, fenpropathrin, fenpyrad, fenpyroximate,
fenthion, fenvalerate, fipronil, fluazinam, flucycloxuron, flucythrinate,
flufenoxuron, flufenprox, fluvalinate, fonophos, formothion, fosthiazate,
fubfenprox, furathiocarb,
HCH, heptenophos, hexaflumuron, hexythiazox,
imidacloprid, iprobenfos, isazophos, isofenphos, isoprocarb, isoxathion,
ivermectin, lambda-cyhalothrin, lufenuron,
malathion, mecarbam, mevinphos, mesulfenphos, metaldehyde, methacrifos,
methamidophos, methidathion, methiocarb, methomyl, metolcarb, milbemectin,
monocrotophos, moxidectin,
naled, NC 184, NI 25, nitenpyram,
omethoate, oxamyl, oxydemeton M, oxydeprofos,
parathion A, parathion M, permethrin, phenthoate, phorate, phosalone,
phosmet, phosphamidon, phoxim, pirimicarb, pirimiphos M, pirimiphos A,
profenofos, promecarb, propaphos, propoxur, prothiofos, prothoate,
pymetrozine, pyrachlophos, pyradaphenthion, pyresmethrin, pyrethrum,
pyridaben, pyrimidifen, pyriproxifen,
quinalphos,
RH 5992,
salithion, sebufos, silafluofen, sulfotep, sulprofos,
tebufenozide, tebufenpyrad, tebupirimphos, teflubenzuron, tefluthrin,
temephos, terbam, terbufos, tetrachlorvinphos, thiafenox, thiodicarb,
thiofanox, thiomethon, thionazin, thuringiensin, tralomethrin,
triarathene, triazophos, triazuron, trichlorfon, triflumuron,
trimethacarb,
vamidothion, XMC, xylylcarb, YI 5301/5302, zetamethrin.
A mixture with other known active compounds, such as herbicides, or with
fertilizers and growth-regulators is also possible.
The active compound according to the invention can furthermore be present
in its commercially available formulations and in the use forms, prepared
from these formulations, as a mixture with synergistic agents. Synergistic
agents are compounds which increase the action of the active compounds,
without it being necessary for the synergistic agent added to be active
itself.
The active compound content of the use forms prepared from the commercially
available formulations can vary within wide limits. The active compound
concentration of the use forms can be from 0.0000001 to 95% by weight of
active compound, preferably between 0.0001 and 1% by weight.
The compounds are employed in a customary manner appropriate for the use
forms.
When used against hygiene pests and pests of stored products, the active
compound has an excellent residual action on wood and clay as well as a
good stability to alkali on limed substrates.
Furthermore, it has been found that the compounds of the formula (I)
according to the invention have a potent insecticidal action against
insects which destroy industrial materials.
The following insects may be mentioned by way of preferred examples but
without any limitation:
Beetles, such as
Hylotrupes bajulus, Chlorophorus pilosis, Anobium punctatum, Xestobium
rufovillosum, Ptilinus pecticornis, Dendrobium pertinex, Emobius mollis,
Priobium carpini, Lyctus brunneus, Lyctus africanus, Lyctus planicollis,
Lyctus linearis, Lyctus pubescens, Trogoxylon aequale, Minthes rugicollis,
Xyleborus spec. Tryptodendron spec. Apate monachus, Bostrychus capucins,
Heterobostrychus brunneus, Sinoxylon spec. Dinoderus minutus
Dermapterans, such as
Sirex juvencus, Urocerus gigas, Urocerus gigas taignus and Urocerus augur.
Termites, such as
Kalotermes flavicollis, Cryptoternes brevis, Heterotermes indicola,
Reticulitermes flavipes, Reticuliternes santonensis, Reticulitermes
lucifugus, Mastotermes darwiniensis, Zootermopsis nevadensis and
Coptotermes formosanus.
Bristletails, such as Lepisma saccharina.
Industrial materials are to be understood as meaning, in the present
context, non-live materials, such as, preferably, synthetic materials,
glues, sizes, paper and board, leather, wood and timber products, and
paint.
The materials to be very particularly preferably protected against attack
by insects are wood and timber products.
Wood and timber products which can be protected by the composition
according to the invention or mixtures comprising such a composition are
to be understood as meaning, for example: construction timber, wooden
beams, railway sleepers, bridge components, jetties, wooden vehicles,
boxes, pallets, containers, telephone poles, wood lagging, windows and
doors made of wood, plywood, particle board, joiner's articles, or wood
products which, quite generally, are used in the construction of houses or
in joinery.
The active compounds can be used as such, in the form of concentrates or
generally customary formulations, such as powders, granules, solutions,
suspensions, emulsions or pastes.
The formulations mentioned can be prepared in a manner known per se, for
example by mixing the active compounds with at least one solvent or
diluent, emulsifier, dispersant and/or binder or fixative, water
repellent, if appropriate desiccants and UV stabilizers and, if
appropriate, colorants and pigments and other processing auxiliaries.
The insecticidal compositions or concentrates used for the protection of
wood and wooden materials comprise the active compound according to the
invention at a concentration of 0.0001 to 95% by weight, in particular
0.001 to 60% by weight.
The amount of the compositions or concentrates employed depends on the
species and the occurrence of the insects and on the medium. The optimum
rate of application can be determined upon use in each case by test
series. However, in general, it suffices to employ 0.0001 to 20% by
weight, preferably 0.001 to 10% by weight, of the active compound, based
on the material to be protected.
The solvent and/or diluent used is an organochemical solvent or solvent
mixture and/or an oily or oil-type organochemical solvent or solvent
mixture of low volatility and/or a polar organochemical solvent or solvent
mixture and/or water and, if appropriate, an emulsifier and/or wetting
agent.
Organochemical solvents which are preferably employed are oily or oil-like
solvents having an evaporation number of above 35 and a flashpoint of
above 30.degree. C., preferably above 45.degree. C. Substances which are
used as such oily and oil-like solvents which have low volatility and are
insoluble in water are suitable mineral oils or their aromatic fractions,
or mineral-oil-containing solvent mixtures, preferably white spirit,
petroleum and/or alkylbenzene.
Substances which are advantageously used are mineral oils with a boiling
range of 170 to 220.degree. C., white spirit with a boiling range of 170
to 220.degree. C., spindle oil with a boiling range of 250 to 350.degree.
C., petroleum or aromatics of boiling range 160 to 280.degree. C., essence
of turpentine and the like.
In a preferred embodiment, liquid aliphatic hydrocarbons with a boiling
range of 180 to 210.degree. C. or high-boiling mixtures of aromatic and
aliphatic hydrocarbons with a boiling range of 180 to 220.degree. C.
and/or spindle oil and/or monochloronaphthalene, preferably
a-monochloronaphthalene, are used.
The organic oily or oil-like solvents of low volatility and having an
evaporation number of above 35 and a flashpoint of above 30.degree. C.,
preferably above 45.degree. C., can be partially replaced by
organochemical solvents of high or medium volatility, with the proviso
that the solvent mixture also has an evaporation number of above 35 and a
flashpoint of above 30.degree. C., preferably above 45.degree. C., and
that the insecticide/fungicide mixture is soluble or emulsifiable in this
solvent mixture.
In a preferred embodiment, part of the organochemical solvent or solvent
mixture is replaced or an aliphatic polar organochemical solvent or
solvent mixture. Substances which are preferably used are aliphatic
organochemical solvents having hydroxyl and/or ester and/or ether groups,
such as, for example, glycol ether, esters and the like.
The organochemical binders used within the scope of the present invention
are the synthetic resins and/or binding drying oils which are known per se
and can be diluted with water and/or are soluble or dispersible or
emulsifiable in the organochemical solvents employed, in particular
binders composed of, or comprising, an acrylate resin, a vinyl resin, for
example polyvinyl acetate, polyester resin, polycondensation or
polyaddition resin, polyurethane resin, alkyd resin or modified alkyd
resin, phenol resin, hydrocarbon resin, such as indene/coumarone resin,
silicone resin, drying vegetable and/or drying oils and/or physically
drying binders based on a natural and/or synthetic resin.
The synthetic resin used as the binder can be employed in the fornm of an
emulsion, dispersion or solution. Up to 10% by weight of bitumen or
bituminous substances can also be used as binder. In addition, colorants,
pigments, water repellents, odour-masking substances and inhibitors or
anticorrosives known per se and the like can also be employed.
The composition or the concentrate preferably comprises, in accordance with
the invention, at least one alkyd resin or modified alkyd resin and/or a
drying vegetable oil as the organochemical binder. Preferably used
according to the invention are alkyd resins with an oil content of over
45% by weight, preferably 50 to 68% by weight.
All or some of the abovementioned binder can be replaced by a fixative
(mixture) or a plasticizer (mixture). These additives are intended to
prevent volatilization of the active compounds and crystallization or
precipitation. They preferably replace 0.01 to 30% of the binder (based on
100% of binder employed).
The plasticizers are from the chemical classes of the phthalic esters, such
as dibutyl phthalate, dioctyl phthalate or benzylbutyl phthalate, the
phosphoric esters, such as tributyl phosphate, the adipic esters, such as
di-(2-ethylhexyl) adipate, the stearates, such as butyl stearate or amyl
stearate, the oleates, such as butyl oleate, the glycerol ethers or
relatively high-molecular-weight glycol ethers, glycerol esters and
p-toluenesulphonic esters.
Fixatives are chemically based on polyvinyl alkyl ethers, such as, for
example, polyvinyl methyl ether, or ketones, such as benzophenone or
ethylenebenzophenone.
Particularly suitable as a solvent or diluent is also water, if appropriate
as a mixture with one or more of the abovementioned organochemical
solvents or diluents, emulsifiers and dispersants.
Particularly effective protection of wood is achieved by large-scale
industrial impregnation processes, for example vacuum, double-vacuum or
pressure processes.
If appropriate, the ready-to-use compositions can additionally comprise
other insecticides and, if appropriate, additionally one or more
fungicides.
Suitable additional components which may be admixed are, preferably, the
insecticides and fungicides mentioned in WO 94/29 268. The compounds
mentioned in that document are expressly incorporated into the present
application.
Very particularly preferred components which may be admixed are
insecticides, such as chlorpyriphos, phoxim, silafluofin, alphamethrin,
cyfluthrin, cypermethrin, deltamethrin, permethrin, imidacloprid, NI-25,
flufenoxuron, hexaflumuron and triflumuron, and fungicides, such as
epoxyconazole, hexaconazole, azaconazole, propiconazole, tebuconazole,
cyproconazole, metconazole, imazalil, dichlorfluanid, tolylfluanid,
3-iodo-2-propinyl-butyl carbamate, N-octyl-isothiazolin-3-one and
4,5-dichloro-N-octylisothiazolin-3-one.
The preparation and the use of the active compounds according to the
invention can be seen from the examples which follow.
PREPARATION EXAMPLES
Example I-1
##STR42##
At 0.degree. C., 5.49 g of ethyldiisopropylamine and subsequently, a little
at a time, 5.19 g of bis-(2-oxo-3-oxazolidinyl)-phosphoryl chloride were
added to a solution of 3.0 g
(2-methyl-1-propylhydrazyl)-carbonyloxy-acetic acid (for example from Ex.
II-1) in 750 ml of dry dichloromethane. The mixture was stirred at
0.degree. C. for 2 h and then allowed to warm to room temperature
overnight. The solution was concentrated and the residue was taken up in
300 ml of ethyl acetate. The solution was washed with semisaturated
NH.sub.4 Cl solution and saturated NaCl solution and dried with sodium
sulphate. The drying agent was filtered off, the solution was concentrated
and the product was purified by column chromatography (stationary
phase:silica gel; mobile phase cyclohexane:ethyl acetate=2:1). This gave
1.70 g (71% of theory) of 3-propyl-4-methyl-1,3,4-oxadianane-2,5-dione as
a yellow-brown oil.
.sup.1 H NMR (500 MHz, CDCl.sub.3) .delta. [ppm]: 0.97 (t, 3H, CH.sub.2
CH.sub.3); 1.62 (sx, 2H, CH.sub.2 CH.sub.3); 3.23 (s, 3H, NCH.sub.3); 3.68
(t, 2H, NH.sub.2); 4.59 (s, 2H, OCH.sub.2)
Examples I-2 to I-15
Similar to Example I-1, the compounds of the formula (I-j) listed in Table
I below were obtained.
TABLE 1
__________________________________________________________________________
##STR43##
(I-j)
Physical data: M.P. o. .sup.1 H-NMR
Ex. No.
R.sup.1 R.sup.3 (CDCl.sub.3): .delta. [ppm]
__________________________________________________________________________
I-2 CH.sub.2 CH(CH.sub.3).sub.2
H 75-77.degree. C.
I-3 (CH.sub.2).sub.3 CH.sub.3
H 27-28.degree. C.
I-4 CH.sub.2 (CH.sub.3).sub.2
H 45-47.degree. C.
I-5
##STR44## H 82-83.degree. C.
I-6 CH.sub.3 H 41-43.degree. C.
I-7
##STR45## H 0.71 (q 2H); 0.73 (q 2H); 1.05 (m 1H);
3.25 (s 3H); 3.58 (d 2H): 4.62 (s 2H)
I-8
##STR46## H 66-69.degree. C.
I-9
##STR47## H 30-32.degree. C.
I-10
(CH.sub.3).sub.3 CCH.sub.2
H 92-93.degree. C.
I-11
CH.sub.2 CH(CH.sub.3).sub.2
##STR48##
70-71.degree. C.
I-12
CH.sub.2 CH(CH.sub.3).sub.2
CH.sub.3 66-67.degree. C.
I-13
##STR49## H 86-88.degree. C.
I-14
##STR50## H 156-158.degree. C.
I-15
##STR51## H 70-72.degree. C.
__________________________________________________________________________
Example I-16
##STR52##
Similar to Example I-1, 5.0 g of
[2-(2-chloro-5-pyridyl)-methyl-1-ethylhydrazyl)-carbonyloxy-acetic acid
(for example from Example II-16) gave 3.33 g (79% of theory) of
4-(2-chloro-5-pyridylmethyl)-3-ethyl-1,3,4-oxadiazine-2,5-dione of melting
point 125-128.degree. C.
Example II-1
##STR53##
4.36 g of benzyl (2-methyl-1-propylhydrazyl)-carbonyloxy-acetate (for
example from Example III-1) were dissolved in 100 ml of ethyl acetate. 100
mg of Pd/C (10%) were added as catalyst and the reaction solution was
hydrogenated at an H.sub.2 pressure of 1 bar. After the reaction had
ended, nitrogen was passed through the solution and the solution was
subsequently freed from catalyst by filtration through diatomaceous earth
(Celite.RTM.). Concentration under reduced pressure gave 3.0 g (100% of
theory) of (2-methyl-1-propylhydrazyl)-carbonyloxy-acetic acid as a brown,
viscous oil. The crude product was reacted further according to Example
I-1 without any purification.
.sup.1 H NMR (500 MHz, CDCl.sub.3) .delta. [ppm]: 0.90 (t, 3H, CH.sub.2
CH.sub.3); 1.65 (m, 2H CH.sub.2 CH.sub.3); 2.65 (br s, 3H; NCH.sub.3);
3.37 (t, 2H, NCH.sub.2); 4.68 (br s, 2H, OCH.sub.2); 6.65 (br s, 2H, NH,
CO.sub.2 H)
Examples II-2 to II-12
Similar to Example II-1, the compounds of the formula (II) listed in Table
2 below were obtained.
TABLE 2
__________________________________________________________________________
##STR54##
(II)
Ex. No.
R.sup.1 R.sup.3 Physical data: .sup.1 H-NMR (CDCl.sub.3):
.delta. [ppm]
__________________________________________________________________________
II-2
CH.sub.2 CH(CH.sub.3).sub.2
H 0.90 (s 2H); 2.05 (m 1H); 2.63 (br s 3H);
3.22 (d 2H); 4.68 (br s 2H)
II-3
(CH.sub.2).sub.3 CH.sub.3
H
II-4
CH.sub.2 (CH.sub.3).sub.2
H 1.17 (d 6H); 2.64 (br s 3H); 4.28 (m 1H);
4.69 (s 2H); 6.0 (br s 2H)
II-5
##STR55## 2.55 (br s 3H); 4.63 (s 2H); 4.71 (s 2H);
6.76 (br s 2H); 7.30 (m 5H)
II-6
CH.sub.3 H 2.63 (br s 3H); 3.12 (br s 3H); 3.90
(br s 2H); 4.69 (s 2H)
II-7
##STR56## H 0.30 (m 2H); 0.50 (m 2H); 1.13 (br m 1H);
2.668 (br s 3H); 3.32 (d 2H); 4.70 (br s
2H)
II-8
##STR57## H 2.60 (br s 3H); 3.20 (br s 2H); 4.75 (s
2H); 7.35 (m 4H)
II-9
##STR58## H 0.85 (2d 9H); 1.05-1.07 (ms 10H); 2.63 (br
s 3H); 3.42 (t 2H); 4.67 (s 2H); 5.40 (br
s 2H)
II-10
(CH.sub.3).sub.3 CCH.sub.2
H 0.95 (s 9H); 2.60 (br s 3H); 3.20 (s 2H);
4.0 (br 2H); 4.68 (br s 2H)
II-11
CH.sub.2 CH(CH.sub.3).sub.2
##STR59##
0.80 (m 6H); 1.90 (br m 1H); 2.50 (br s
3H); 3.10 (m 4H); 4.0 (br 2H); 7.28 (m
5H)
II-12
CH.sub.2 CH(CH.sub.3).sub.2
CH.sub.3 0.95 (m 9H); 1.55 (m 1H); 2.80 (br s 3H);
3.35 (m 2H); 5.10 (m 1H); 5.75 (br s,
__________________________________________________________________________
2H)
Example II-13
##STR60##
At 0.degree. C., 50.5 g of trifluoroacetic acid were added dropwise to a
solution of 10 g of tert-butyl
[2-tert-butoxycarbonyl-2-methyl-1-(3-thienylmethyl)-hydrazyl]-carbonyloxy-
acetate (for example from Example IV-13) in 100 ml of dry dichloromethane.
After 2 h, the mixture was allowed to warm to room temperature and the
completeness of the reaction was checked by TLC (silica gel,
cyclohexane:ethyl acetate=2:1). Under reduced pressure, the solution, with
added dichloromethane, was repeatedly concentrated to remove the acid
(ultimately at high vacuum). This gave 12.56 g of
2-methyl-1-(3-thienylmethyl)-hydrazyl-carbonyloxy-acetic acid as a brown,
viscous oil. The crude product was reacted further according to Example
I-13 without purification.
.sup.1 H NMR (500 MHz, CDCl.sub.3) .delta. [ppm]: 2.83 (br s, 3H
NCH.sub.3); 4.80 and 4.90 (2s, 2.times.2H, NCH.sub.2, OCH.sub.2); 7.10 (m,
1H, arom); 7.35 (m, 1H, arom); 7.40 (m, 1H, arom.); 7.63 (br s, 2H, NH,
CO.sub.2 H)
Example II-14
##STR61##
2.5 g of benzyl
[2-benzyloxycarbonyl-2-methyl-1-(3-indolylmethyl)-hydrazyl]-carbonyloxy-ac
etate (for example from Ex. IV-14) were dissolved in 30 ml of ethanol. 50
mg of Pd/C (10%) were added as catalyst, and the reaction solution was
then hydrogenated using an H.sub.2 pressure of 1 bar. After the reaction
had ended, nitrogen was passed through the solution which was subsequently
freed from the catalyst by filtration through diatomaceous earth
(Celite.RTM.). The mixture was concentrated under reduced pressure, giving
1.3 g (95% of theory) of [1-(3-indolyl)-2-methyl-hydrazyl]-carbonyloxy
acetic acid of melting point 50-53.degree. C. The crude product was
reacted further according to Example I-14 without purification.
.sup.1 H NMR (500 MHz, CDCl.sub.3) .delta. [ppm]: 2.65 (br s, 3H,
NCH.sub.3); 4.80 (2s, 4H, OCH.sub.2, NCH.sub.2); 7.0-8.2 (m, 6H, NH, arom)
Example II-15
##STR62##
By the method of Example II-14, benzyl
[2-benzyloxycarbonyl-2-methyl-1-(2,2-dimethyl-1,3-dioxo-4-yl)-methyl-2-met
hyl-hydrazyl]-carbonyloxy-acetate (for example from Example IV-15) gave
[1-(2,2-dimethyl-1,3-dioxo-4-yl)-methyl-2-methyl-hydrazyl]-carbonyloxy-ace
tic acid.
.sup.1 H NMR (500 MHz, CDCl.sub.3) .delta. [ppm]: 1.35 u. 1.43 (2s,
2.times.3H, C(CH.sub.3).sub.2); 2.63 (br s, 3H, NCH.sub.3); 3.60 (br m,
2H, NCH.sub.2); 3.84 (br m, 1H, OCHCH.sub.2); 4.08 u. 4.37 (2 br m,
2.times.1H, OCH.sub.2 CH); 4.68 (br m, 2H, CO--CH.sub.2 O); 6.0 (br s, 2H,
NH, CO.sub.2 H).
Example II-16
##STR63##
By the method of Example II-13, 7.52 g of tert-butyl
[2-tert-butoxycarbonyl-2-(2-chloro-5-pyridyl)-methyl-1-ethyl-hydrazyl]-car
bonyloxy-acetate (for example from Example IV-16) gave 4.9 g (100% of
theory) of
[2-(2-chloro-5-pyridyl)-methyl-1-ethylhydrazyl]-carbonyloxy-acetic acid.
.sup.1 H NMR (500 MHz, CDCl.sub.3) .delta. [ppm]: 1.10 (br t, 3H, CH.sub.2
CH.sub.3); 3.30 (br s, 2H, NCH.sub.2); 4.10 (br s, 2H, NCH.sub.2); 4.72
(s, 2H, OCH.sub.2); 7.43/7.89/8.38 (3 m, 3.times.1H, arom).
Example III-1
##STR64##
At 0.degree. C., 16.9 g of trifluoroacetic acid were added dropwise to a
solution of 6.65 g of benzyl
(2-tert-butoxycarbonyl-2-methyl-1-propylhydrazyl)-carbonyloxy-acetate (for
example from Ex. IV-1) in 50 ml of dry dichloromethane. The solution was
stirred at 0.degree. C. for 2 to 3 h and allowed to warm to RT overnight.
The reaction solution was concentrated under reduced pressure. The residue
was taken up in 300 ml of ethyl acetate and washed with saturated sodium
bicarbonate and saturated sodium chloride solution. The organic phase was
dried over sodium sulphate, the drying agent was filtered off and the
filtrate was concentrated under reduced pressure. This gave 4.76 g (100%
of theory) of benzyl (2-methyl-1-propylhydrazyl)-carbonyloxy-acetate as a
brown viscous oil. The crude product was reacted further according to
Example II-1 without purification.
.sup.1 H NMR (500 MHz, CDCl.sub.3) .delta. [ppm]: 0.88 (t, 3H, CH.sub.2
CH.sub.3); 1.64 (sx, 2H, CH.sub.2 CH.sub.3); 2.60 (br s, 3H, NCH.sub.3);
3.35 (t, 2H, CH.sub.2 CH.sub.3); 4.69 (br s, 2H, CH.sub.2 Ph); 5.20 (s,
2H, OCH.sub.2), 7.37 (m, SH, arom.)
Examples III-2 to III-12
By the method of Example III-1, the compounds of the formula (X) listed in
Table 3 below were obtained.
TABLE 3
__________________________________________________________________________
##STR65##
(X)
Ex. No.
R.sup.1 R.sup.3
Physical data: .sup.1 H-NMR (CDCl.sub.3): .delta.
[ppm]
__________________________________________________________________________
III-2
CH.sub.2 CH(CH.sub.3).sub.2
H 0.88 (d 6H); 1.55 (br s 1H); 2.03 (sp 1H);
2.60 (br s 3H); 3.20 (d 2H); 4.70 (m 2H);
5.20 (s 2H); 7.35 (m 5H)
III-3
(CH.sub.2).sub.3 CH.sub.3
H 0.92 (t 3H); 1.30 (m 2H); 1.58 (qn 2H);
2.60 (br s 3H); 3.48 (t 2H); 4.70 (br s 2H);
5.20 (s 2H); 7.35 (m 5H)
III-4
CH.sub.2 (CH.sub.3).sub.2
H 1.15 (d 6H); 1.55 (br s 1H); 2.62 (br s
3H); 4.25 (br s 1H); 4.70 (s 2H); 5.19 (s
2H); 7.35 (m 5H)
III-5
##STR66## H 1.55 (br s 1H); 2.53 (br s 3H); 4.10 (s 2H);
4.24 (s 2H); 5.21 (s 2H); 7.30 (m 10H)
III-6
CH.sub.3 H 2.60 (br s 3H); 2.90 (br s 1H); 3.10 (br s
3H); 4.69 (s 2H); 5.20 (s 2H); 7.35 (m
5H)
III-7
##STR67## H 0.28 (m 2H); 0.47 (m 2H); 1.12 (m 1H); 2.65 (br
s 3H); 3.28 (d 2H); 4.70 (br s 2H); 5.20 (br s
2H); 7.35 (m 5H)
III-8
##STR68## H 2.54 (br s 3H); 4.30 (br s 1H); 4.53 (s 2H);
4.73 (s 2H); 5.22 (s 2H); 7.35 (m 9H)
III-9
##STR69## H
III-10
(CH.sub.3).sub.3 CCH.sub.2
H 0.93 (s 9H); 2.57 (br s 3H); 3.19 (s 2H);
4.68 (br m 2H); 5.20 (s 2H); 7.35 (m 5H)
III-12
CH.sub.2 CH(CH.sub.3).sub.2
CH.sub.3
0.90 (2d 6H); 1.53 (d 3H); 2.70 (br s
3HH); 3.27 (m 2H); 5.18 (m 3H); 7.35
(m 5H)
__________________________________________________________________________
Example IV-1
##STR70##
For about 1 h, carbon dioxide gas was introduced into a suspension of 22.80
g of caesium carbonate and 6.55 g of
1-tert-butoxycarbonyl-1-methyl-2-propyl-hydrazine in 140 ml of dry
dimethylformamide. 8.02 g of benzyl bromoacetate were then slowly added in
a dropwise fashion, and carbon dioxide was introduced for a further 30-45
min. The reaction mixture was stirred overnight and then poured into 300
ml of semisaturated sodium chloride solution and extracted with
3.times.150 ml of ethyl acetate. The organic phase was dried over sodium
sulphate, the drying agent was filtered off and the filtrate was
concentrated under reduced pressure at a temperature of not more than
50.degree. C. The product was purified by column chromatography (silica
gel; cyclohexane:ethyl acetate=5:1). This gave 8.9 g (67% of theory) of
benzyl
(2-tert-butoxycarbonyl-2-methyl-1-propylhydrazyl)-carbonyloxy-acetate as a
light-yellow viscous oil.
.sup.1 H NMR (500 MHz, CDCl.sub.3) .delta. [ppm]: 0.93 (t, 3H, CH.sub.2
CH.sub.3); 1.47 (ms, 9H, C(CH.sub.3).sub.3 ; 1.63 (m, 2H, CH.sub.2
CH.sub.3); 2.90-3.55 (ms, SH, NCH.sub.2, NCH.sub.3); 4.40-5.25 (ms, 4H,
CH.sub.2 Ph, OCH.sub.2); 7.36 (m, 5H, C.sub.5 H.sub.5)
Example IV-2
##STR71##
At 0-5.degree. C., a solution of 25.63 g of benzyl D-phenyllactate and
11.13 g of triethylamine in 130 ml of dry tetrahydrofuran was added
dropwise over a period of 1 h to a solution of 19.8 g of phosgene in 100
ml of toluene. The mixture was then stirred at 0.degree. C. for about 30
min. and at room temperature for 1 h. Precipitated solid was filtered off
and the solution was concentrated under reduced pressure. The resulting
crude chloroformate was taken up in 50 ml of dry tetrahydrofuran and added
dropwise over a period of 1-2 h to a solution of 20.24 g of
1-tert-butoxycarbonyl-1-methyl-2-sec-butyl-hydrazine and 10.12 g of
triethylamine in 70 ml of dry tetrahydrofuran which had been cooled to
0.degree. C. The mixture was subsequently allowed to warm to room
temperature and stirred overnight. The reaction solution was added to 200
ml of semisaturated sodium chloride solution and extracted with
3.times.150 ml of ethyl acetate. The organic phase was dried over sodium
sulphate, the drying agent was filtered off and the filtrate was
concentrated under reduced pressure. The product was purified by column
chromatography (silica gel; cyclohexane:ethyl acetate=10:1). This gave
36.83 g (76% of theory) of benzyl
1-(2-tert-butoxycarbonyl-2-methyl-1-sec-butyl-hydrazyl)-carbonyloxy-2-phen
ylpropionate as a light-yellow viscous oil.
.sup.1 H NMR (500 MHz, CDCl.sub.3) .delta. [ppm]: 0.90 (ms, 6H,
CH(CH.sub.3).sub.2); 1.30-1.75 (ms, 10H, CH(CH.sub.3).sub.2,
C(CH.sub.3).sub.3); 2.60-3.40 (ms, 6H, OCH, NCH.sub.2, NCH.sub.3);
5.0-5.40 (ms, 4H, 2 CH.sub.2 Ph); 7.25 (m, 10H, 2 C.sub.6 H.sub.5)
Examples IV-3 to IV-12
By the methods of Examples IV-1 and IV-2, the compounds of the formula
(XII) listed in Table 4 below were obtained.
TABLE 4
__________________________________________________________________________
##STR72##
(XII)
Physical data: M.p. o. .sup.1 H-NMR
Ex. No.
R.sup.1 R.sup.3
(CDCl.sub.3): .delta. [ppm]
__________________________________________________________________________
IV-3
CH.sub.2 CH(CH.sub.3).sub.2
H 0.95 (2d 6H); 1.45 (4s 9H); 1.95 (m 1H);
3.0-3.4 (ms 5H); 4.4-5.25 (ms 4H); 7.35
(m, 5H)
IV-4
(CH.sub.2).sub.3 CH.sub.3
H 0.95 (m 3H); 1.30-1.60 (m 13H); 3.05-
3.65 (m 5H); 4.4-5.3 (m 4H); 7.35 (m 5H)
IV-5
CH.sub.2 (CH.sub.3).sub.2
H 1.20 (2d 6H); 1.45 (ms 9H); 3.08 (m 3H);
4.3-5.25 (ms 5H); 7.35 (m 5H)
IV-6
##STR73## H 1.35-1.55 (ms 9H); 2.80 (ms 3H) 4.30- 5.30 (ms
6H); 7.35 (ms 10H)
IV-7
CH.sub.3 H 1.45 (ms 9H); 3.0-3.20 (ms 6H); 4.40-
5.30 (ms 4H); 7.35 (ms 5H)
IV-8
##STR74## H 0.25 (m; 2H); 0.55 (m 2H); 1.05 (m 1H); 1.45 (ms
9H); 3.10-3.65 (ms 5H); 4.40- 5.30 (ms 4H); 7.35
(m 5H)
IV-9
##STR75## H 1.45 (ms 9H); 2.85 (ms 3H); 4.25-5.30 (ms 6H);
7.15-7.50 (m 9H)
IV-10
##STR76## H 0.88 (ms 9H); 1.05-1.70 (ms 19H); 3.07 (m 3H);
3.35-3.70 (m 2H); 4.40-5.30 (ms 4H); 7.35 (m
5H)
IV-11
(CH.sub.3).sub.3 CCH.sub.2
H 0.95 (s 9H); 1.45 (ms 9H); 3.0-3.5 (ms
5H); 4.35-5.25 (ms 4H); 7.35 (m 5H)
IV-12
CH.sub.2 CH(CH.sub.3).sub.2
CH.sub.3
0.9-1.15 (ms 6H); 1.50 (m 12H); 1.90 (m
1H); 3.0-3.45 (ms 5H); 5.0-5.25 (ms 3H);
7.45 (m 5H)
__________________________________________________________________________
Example IV-13
##STR77##
Carbon dioxide gas was introduced into a suspension of 22.80 g of caesium
carbonate in 140 ml of dry dimethylformamide for about 20 min.
Subsequently, 8.47 g of
1-tert-butoxycarbonyl-1-methyl-2-(3-thienylmethyl)-hydrazine were slowly
added dropwise. Carbon dioxide was introduced for a further 60 min., 6.83
g of tert-butyl bromoacetate were then slowly added dropwise and carbon
dioxide was introduced for a further 30-45 min. The reaction mixture was
stirred overnight and then added to 200 ml of semisaturated sodium
chloride solution and extracted with 3.times.150 ml of ethyl acetate. The
organic phase was dried over sodium sulphate, the drying agent was
filtered off and the filtrate was concentrated under reduced pressure at a
temperature of not more than 50.degree. C. The product was purified by
column chromatography (silica gel; cyclohexane:ethyl acetate=5:1). This
gave 14.1 g (100% of theory)
oftert-butyl-[2-tert-butoxycarbonyl-2-methyl-1-(3-thienylmethyl)-hydrazyl]
-carbonyloxy-acetate.
.sup.1 H NMR (500 MHz, CDCl.sub.3) .delta. [ppm]: 1.35-1.55 (m, 18H,
2.times.C(CH.sub.3).sub.3); 2.87 (m, 3H, NCH.sub.3); 4.25-5.05 (ms, 4H,
OCH.sub.2, NCH.sub.2); 7.20 (m, 3H, arom.)
Example IV-14
##STR78##
By the method of Example IV-1, 10.8 g of
1-benzyloxycarbonyl-1-methyl-2-(3-indolylmethyl)-hydrazine and 8.02 g of
benzyl bromoacetate gave, in three fractions, 6.41 g of pure and 7.04 g of
slightly impure (76% of theory) benzyl
[2-benzyloxy-carbonyl-2-methyl-1-(3-indolylmethyl)-hydrazyl]-carbonyloxy-a
cetate.
.sup.1 H NMR (500 MHz, CDCl.sub.3) .delta. [ppm]: 2.83 (m, 3H, NCH.sub.3);
4.10-5.35 (ms 6H, NH.sub.2, OCH.sub.2, CH.sub.2 Ph); 7.35 (m, 15H, arom);
8.05 (br s, 1H, NH)
Example IV-15
##STR79##
By the method of Example IV-1,
1-benzyloxycarbonyl-1-methyl-2-(2,2-dimethyl-1,3-dioxo-4-yl)-methyl-hydraz
ine and benzyl bromoacetate gave benzyl
[2-benzyloxy-carbonyl-2-methyl-1-(2,2-dimethyl-1,3-dioxo-4-yl)-methyl-2-me
thyl-hydrazyl]-carbonyloxy-acetate.
.sup.1 H NMR (500 MHz, CDCl.sub.3) .delta. [ppm]: 1.23 to 1.43 (m, 6H,
C(CH.sub.3).sub.2 ; 3.12-3.20 (m 3H, NCH.sub.3); 3.25-4.97 (m, 7H,
OCH.sub.2, NCH.sub.2, NCH.sub.2 CH, OCHCH.sub.2 O); 5.17 (m, 4H,
2.times.CH.sub.2 Ph); 7.35 (m, 1H, arom).
Example IV-16
##STR80##
By the method of Example IV-13, 7.13 g of
1-tert-butoxycarbonyl-1-(2-chloro-5-pyridyl)-methyl-2-ethyl-hydrazine and
4.87 g of tert-butyl bromoacetate gave 955 g (86% of theory) of tert-butyl
[2-tert-butoxycarbonyl-2-(2-chloro-5-pyridyl)-methyl-1-ethylhydrazyl]-carb
onyloxy-acetate.
.sup.1 H NMR (500 MHz, CDCl.sub.3): 1.0 (m, 3H, CH.sub.3 CH.sub.2); 1.47
(ms, 18H, 2.times.C(CH.sub.3).sub.3); 3.15-3.45 (ms, 2H, NCH.sub.2);
4.05-5.0 (ms, 4H, NCH.sub.2, OCH.sub.2); 7.30/7.75/8.40 (3m, 3.times.1H,
arom).
Use Examples
Example A
Haemonchus contortus/sheep
Sheep experimentally infected with Haemonchus contortus were treated after
expiry of the prepatency time of the parasite.
The active compounds were administered orally in gelatin capsules as pure
active compound.
The efficacy is determined by quantitatively counting the nematode eggs
excreted with the faeces before and after treatment.
Complete cessation of oviposition after treatment means that the nematodes
have been expelled or are so damaged that they no longer produce eggs
(effective dose).
The following results were obtained:
______________________________________
Active compound effective dose
Example No. in mg/kg
______________________________________
I-2 5
I-3 5
I-11 5
______________________________________
Example B
Plutella test
Solvent: 7 parts by weight of dimethylformamide
Emulsifier: 1 part by weight of alkylaryl polyglycol ether
To produce a suitable preparation of active compound, 1 part by weight of
active compound is mixed with the stated amount of solvent and the stated
amount of emulsifier, and the concentrate is diluted with water to the
desired concentration.
Cabbage leaves (Brassica oleracea) are treated by being dipped into the
preparation of active compound of the desired concentration and populated
with caterpillars of the diamond-back moth (Plutella maculipennis) while
the leaves are still moist.
After the desired period of time, the kill in % is determined. 100% means
that all the caterpillars have been killed; 0% means that none of the
caterpillars have been killed.
In this test, for example the compound of Preparation Example I-2
exhibited, at an exemplary active compound concentration of 0.1%, a kill
of 100% after 7 days.
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